Cytokinetic, Incorporated v Curis, Inc
[2011] APO 66
•23 August 2011
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Cytokinetic, Incorporated v Curis, Inc. [2011] APO 66
Patent Application: 780846
Title:Mediators of Hedgehog Signalling Pathways, Compositions and Uses Related Thereto
Patent Applicant: Curis, Inc.
Opponent:Cytokinetics, Incorporated
Delegate:Ms Nicole Howard
Decision Date: 23 August 2011
Hearing Date: 23 May 2011 in Canberra
Catchwords: PATENTS - section 59 - opposition to grant of a patent – claims not novel – claims not fairly based – opposed specification does not anticipate itself – library of compounds publicly available – opposition succeeds – costs awarded against applicant
Representation: Patent applicant: Andrew Fox of Counsel, instructed by Ivan Rajkovic, Patent Attorney of Shelston IP, Sydney
Opponent:Matthew Lucas, Patent Attorney of Davies Collison Cave, Sydney and by William Pickering, Patent Attorney of Davies Collison Cave, Sydney
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 780846
Title:Mediators of Hedgehog Signalling Pathways, Compositions and Uses Related Thereto
Patent Applicant: Curis, Inc.
Date of Decision: 23 August 2011
DECISION
The opposition succeeds on grounds of novelty, fair basis and clarity. Costs awarded against the applicant.
REASONS FOR DECISION
Background
Patent application 780846 (‘hereafter the application’) was filed under the PCT (WO2001/019800) by Curis, Inc. (hereafter ‘Curis’) on 15 September 2000. It claims priority from
· US 60/154 526 filed on 16 September 1999
· US 60/159 412 filed on 14 October 1999
· US 60/162899 filed on 1 November 1999
After several rounds of amendments the specification was accepted on 25 February 2005.
A notice of opposition to grant of a patent was filed on 21 July 2005 by Cytokinetics, Incorporated (hereafter ‘Cytokinetics’), followed by a statement of grounds and particulars (hereafter ‘SGP’) on 21 October 2005. On 12 February 2007 amendments to the SGP were allowed.
Evidence
Evidence in support was completed on 12 October 2007, consisting of Statutory Declarations by
·Associate Professor Joseph Attila Rothnagel dated 26 October 2006 (Rothnagel No. 1) together with Exhibits JAR-1 and JAR-3
·Associate Professor Joseph Attila Rothnagel dated 22 June 2007 (Rothnagel No. 2) together with Exhibits JAR-4 to JAR-6
·Dr Craig Williams dated 28 February 2007 (Williams) together with Exhibits CW-1 to CW-13
·Professor Curt Wentrup dated 31 May 2007 (Wentrup) together with Exhibits CW-1 to CW-8
·Dr William John Pickering dated 15 October 2007 (Pickering) together with Exhibits WJP-1 to WJP-3. WJP-1, WJP-2 and WJP-3 are declarations made by Dr Jeffery T Finer, designated Finer 1, Finer 2 and Finer 3 respectively. The Finer declarations were made in relation to Cytokinetic’s opposition to European Patent No 127268.
Evidence in answer was completed on 15 March 2010, consisting of Statutory Declarations by
·Dr Ivan Alexander Rajkovic dated 10 November 2009 (Rajkovic) together with Exhibit IAR-1 which is a declaration by Frederic de Sauvage (Sauvage). Sauvage further includes Exhibits FD-1 to FD-6.
·Dr William Denny dated 14 January 2010 (Denny) together with Exhibits WAD-1 to WAD-7
·Dr Stephen E Gould dated 9 March 2010 (Gould) together with Exhibits SEG-1 to SEG-6
Evidence in reply was completed on 16 June 2010, consisting of a Statutory Declaration by
·Dr Mathew Allan Lucas dated 16 June 2010 (Lucas) together with Exhibit MAL-1
Further evidence was served on 10 February 2011, consisting of a Statutory Declaration by
·Dr Brian L Buckwalter dated 3 February 2011 (Buckwalter) together with Exhibits BLB-1 and BLB-2
No evidence in response was served.
During the opposition process, on 6 July 2009 and 26 August 2009 amended claims (of narrower scope) were filed. It is noted that this was after the completion of evidence in support.
Grounds of Opposition
At the hearing Cytokinetics limited the number of prior art documents relied on to four (4). The grounds relied upon by the Opponent are:
·Lack of Novelty
·Lack of Inventive Step
·Lack of manner of manufacture
·Failure to comply with s.40 (fair basis, clarity)
·Utility
The specification
The description
Members of the hedgehog family of signalling molecules mediate many important short and long range patterning processes during invertebrate and vertebrate development. The application describes allegedly novel small molecules, compositions containing them and methods for inhibiting abnormal growth states of cells resulting from activation of this signalling pathway. The specification broadly designates the small molecules as Formula I and Formula II and goes on to describe preferred compounds and their synthesis. The molecules may be identified by mass screening.
The application explains that signal transduction pathways regulated by hedgehog (for example ptc, gli or smoothened) can be inhibited by small molecules and suggests the activation of various receptors may be the mechanism by which these agents act. It is specifically contemplated that the molecules will be capable of inhibiting proliferation (or other biological consequences) in cells having a hedgehog ‘gain-of-function’ phenotype. The term ‘gain-of-function’ is defined as any similar cellular phenotype which occurs due to an alteration anywhere in the hedgehog signal transduction pathway, including, but not limited to, a modification or mutation of hedgehog (gene) itself. For example, a tumor cell with an abnormally high proliferation rate due to activation of the hedgehog signalling pathway would have a ‘hedgehog gain-of function’ phenotype, even if hedgehog is not mutated in that cell.
Further disclosed are methods for inhibiting unwanted hair growth and methods for treating cancer. The methods are not limited to inhibiting/treating hair growth or cancer that is necessarily related to alteration of hedgehog signalling pathways. These more general methods became part of the specification as the result of amendments filed 16 September 2004 and are in the form of consistory statements.
The claims as proposed to be amended
The accepted specification (including the amendments proposed during opposition) ends with 76 claims. They define compounds of the invention and their uses in treatment of various conditions, including inhibition of cell proliferation, methods of inhibiting hair growth and treatment of cancer. They may be grouped as follows:
Claims 1-5 A method for inhibiting an altered growth state of a cell having hedgehog gain-of-function phenotype, comprising contacting the cell with a compound in a sufficient amount to inhibit the altered growth state, wherein the compound is an organic molecule represented in the general formula (II): 6-7 A method of inhibiting unwanted hair growth in an animal, …formula (II) 8-26 A method for treating cancer…formula (II) 27-32 Use of a compound of formula (II) in the preparation of a pharmaceutical composition for treating cancer in an animal… 33-48 Use of a compound of formula (II) in the preparation of a pharmaceutical composition for treating unwanted hair growth in an animal… 49 A compound having a structure selected from the structures depicted in Figures 32j, k, l …or a pharmaceutically acceptable salt therof. 50-66 A compound represented by general formula (II)…provided that the compound is not any one of the following:… 67 A pharmaceutical preparation comprising a sterile pharmaceutical excipient and the compound of any one of claims 50-66. 68-70 Dependent omnibus claims 71-76 Further compound claims dependant on claim 50 General Formula (II) is of the following structure.
Claims 1, 6, 8, 27 and 33
Independent method/use claims 1, 6, 8, 27 and 33 provide the following definitions for the substituents of Formula II:
·R1 and R2, independently for each occurrence, represent H, lower alkyl (substituted or unsubstituted), aryl (substituted or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted);
·L adjacent to X is –CH(R10)- where R10 is substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl or aralkyl;
·L, adjacent to R1 and L adjacent to R2, independently for each occurrence, are absent or are (CH2)n-alkyl-, -alkenyl-, -alkynyl-, -(CH2)nalkenyl-, -(CH2)nalkynyl-, (CH2)nO(CH2)p-, -(CH2)nNR2(CH2)p-, -(CH2)nNR2(CH2)p-, (CH2)nS(CH2)p-, (CH2)nalkenyl(CH2)p-, (CH2)nalkynyl(CH2)p-, -O(CH2)n-, NR2(CH2)n or S(CH2)n, any of which are optionally substituted with substituted or unsubstituted lower alkyl, alkenyl, or alkynyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl;
·X is –N(R12)-, where R12 is substituted or unsubstituted lower alkyl;
·Y is –C(=O)-, -C(=S)-, -S(O2)-, -S(O)-, -C(=NCN)-, -P(=O)(OR2)-, a heteroaromatic group, or a direct bond between X and Z;
·Z is –N(R8)-, -O-, -S-, -Se-, -N=N-, -ON-CH-, -R8N-NR8-, ONR8-, a heterocyclic group, or a direct bond between Y and L;
·R8, independently for each occurrence is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl, or two R8 groups taken together may form a 4- to 8- membered ring, together with the atoms to which they are attached, which ring may include one or more carbonyls;
·W is a substituted or unsubstituted benzene ring fused to the pyrimidone ring;
·P represents, independently for each occurrence, an integer form 0 to 10; and n, individually for each occurrence, represents an integer from 0 to 10; or a pharmaceutically acceptable salt thereof.
Claim 50
Independent compound claim 50 provides the following definitions for the substituents of Formula II.
·R1 represents a substituted or unsubstituted aryl or heteroaryl group;
·R2 independently for each occurrence, represents H, lower alkyl (substituted or unsubstituted), aryl (substituted or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted);
·L adjacent to X is –CH(R10)- where R10 is substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl or aralkyl;
·L, adjacent to R1 and L adjacent to R2, independently for each occurrence, are absent or are (CH2)n-alkyl-, -alkenyl-, -alkynyl-, -(CH2)nalkenyl-, -(CH2)nalkynyl-, (CH2)nO(CH2)p-, -(CH2)nNR2(CH2)p-, -(CH2)nNR2(CH2)p-, (CH2)nS(CH2)p-, (CH2)nalkenyl(CH2)p-, (CH2)nalkynyl(CH2)p-, -O(CH2)n-, NR2(CH2)n- or S(CH2)n-, any of which are optionally substituted with substituted or unsubstituted lower alkyl, alkenyl, or alkynyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaralkyl;
·X is –N(R12)-, where R12 is substituted or unsubstituted lower alkyl;
·Y is –C(=O)-, -C(=S)-, or a heteroaromatic group;
·Z is –N(R8)-, -O-, -S-, a heterocyclic group, or a direct bond between Y and L;
·R8, independently for each occurrence is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl, or two R8 groups taken together may form a 4- to 8- membered ring, together with the atoms to which they are attached, which ring may include one or more carbonyls;
·W is a substituted or unsubstituted benzene ring fused to the pyrimidone ring;
·p represents, independently for each occurrence, an integer form 0 to 10; and n, individually for each occurrence, represents an integer from 0 to 10; or a pharmaceutically acceptable salt thereof;
·provided that when L in -L-R1 is absent and R1 is a substituted aryl, R1 is not substituted with an isopropoxy ((CH3)2CHO-) group;
·Claim 50 further specifically excludes 17 compounds which are provided as structural drawings within the claim. It is not necessary to reproduce them here.
The dependent claims contain further provisos and will be referred to as necessary.
Claim Construction
The construction of the claims is not in dispute. I do note however that page 30 of the specification (as filed) provides that the
“term ‘alkyl’ refers to the radical of saturated aliphatic groups, including straight chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups and cycloalkyl-substituted groups.”
and on page 31, paragraph 1 of the specification ‘lower alkyl’ is specified as having from one to ten carbon atoms (which may or may not be substituted). Accordingly I have construed the claims as importing these definitions. I further note that independent method/use claims 6, 8, 27 and 33 are not limited to hedgehog signalling pathways and none of the claims limit the compounds of Formula II to hedgehog antagonists. It follows that these claims include within their scope methods/uses related to non-hedgehog pathways using compounds of Formula II that may not be hedgehog antagonists.
Onus of proof
In proceedings such as these before the Commissioner, the onus rests with the opponent to clearly establish its case in reaching a conclusion on any issue. In F. Hoffman-La Roche AG v New England Biolabs Inc [2000] FCA 283, Emmett J of the Federal Court found that in opposition proceedings, the Court (and by implication the Commissioner of Patents in her role as a tribunal) should be "clearly satisfied that the patent, if granted, would not be valid". Where questions of fact such as obviousness and existence of invention are involved "the grant should not be refused unless it has been clearly shown that the grounds of opposition have been clearly made out" (Montecatini v Eastman Kodak (1971) 45 ALJR 593).
Fair basis
The general test for fair basis set out in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58 at [69]; (2004) 217 CLR 274 at 300 [69] requires that there be a
‘real and reasonably clear disclosure in the body of the specification of what is then claimed, so that the alleged invention as claimed is broadly, that is to say in a general sense, described in the body of the specification.’
The opponent contends that claims 6-9, 11-23, 27, 28, 30-45, 68 and 69 are not fairly based on the matter described in the specification.
Cytokinetics points to the title, abstract, background to the invention, object of the invention, detailed description and examples as limiting the real and reasonable disclosure to that related to growth states resulting from activation of the hedgehog signalling pathway, such as hedgehog gain-of-function phenotype. They argue that claims generally directed to the treatment of ‘cancer’ and ‘unwanted hair growth’ travel beyond that which is disclosed in the body of the specification. Curis respond that hedgehog signalling pathways are only stated as the invention ‘in general terms’ and that consistory clauses mirror the contested claims. The evidence relating to the fair basis of the claims is limited.
Denny declares at [1.10]
‘The patent application concerns methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function mutations, by the application of compounds that can antagonize hedgehog activity or agonise a normal ptc pathway.’
While Rothnagel (No 2) declares at [3.2]
‘The Opposed Application is generally directed to a method for inhibiting altered growth states in cells having a hedgehog gain-of-function phenotype by contacting the cell with a hedgehog antagonist in a sufficient amount to inhibit the altered growth state.’
Denny is clear in his understanding of what the application concerns. Rothnagel refers to the ‘general’ direction of the application being that of the hedgehog kind, and his declaration goes on to discuss the specification in terms of hedgehog pathway signalling only. He does not refer in any way to non-hedgehog pathway methods or uses. This evidence seems to indicate that the body of the specification only provides a real and reasonable disclosure of methods/uses directed to hedgehog pathway related signalling and does not extend to that of non-hedgehog pathway methods. However, to be satisfied I think it useful to refer to the specification.
The High Court noted in Lockwood (supra) at [99]
‘Doric submitted that Olin decided that a claim based on a consistory clause cannot be fairly based. It did not. Rather, as the Patentee submitted, the correct position is that a claim based on what has been cast in the form of a consistory clause is not fairly based if other parts of the matter in the specification show that the invention is narrower than that consistory clause. The inquiry is into what the body of the specification read as a whole discloses as the invention [117]. An assertion by the inventor in a consistory clause of that of which the invention consists does not compel the conclusion by the court that the claims are fairly based nor is the assertion determinative of the identity of the invention. The consistory clause is to be considered by the court with the rest of the specification.’
Curis acknowledge that the claims in question are mirrored by consistory clauses. I agree. They further contend that nothing in the body of the specification suggests that the description of the invention is narrower than the invention claimed. It is this contention I do not agree with. On inspection of the specification (as amended, as originally filed or in priority documents) I cannot find any disclosure of non-hedgehog pathway related treatments nor any suggestion that the invention extends to such treatments. The description refers to ‘the subject method’ of the invention being useful to treat many kinds of cancer and unwanted hair growth, however the ‘subject method’ is only described as the use of mediators in inhibiting aberrant growth states resulting from activation of the hedgehog signalling pathway. Since the only disclosure in support of claims to general methods for treating cancer and unwanted hair growth is found in the consistory clauses the requirements for fair basis have not been satisfied.
I find that claims 6-9, 11-23, 27, 28, 30-45, 68 and 69 are not fairly based.
Priority Dates
Section 114 provides that:
‘where a claim of a complete specification claims matter that was not in substance disclosed as a result of amending the specification, the priority date of the claim must be determined under the regulations.’
Regulation 3.14 provides that:
‘If subsection 114(1) of the Act applies to a claim of a specification, the priority date of the claim is:
(a) In the case of an amendment to which subsection 89(4) or (5) of the Act applies – the date on which the amendment is taken to have been made under that subsection; and
(b) In any other case – the date of filing of the statement of proposed amendments that resulted in the disclosure referred to in subsection 114(1) of the Act.’
Regulation 3.14(b) is relevant to these proceedings.
Cytokinetics argues that by adding various limitations and provisos relating to General Formula II, the claims as proposed to be amended claim matter not in substance disclosed in the specification as filed, and therefore these claims should be afforded the priority date of their filing (6 July 2009 and 26 August 2009).
In the absence of evidence addressing this matter, a simple comparison of the specification as filed with the present claims demonstrates a real and reasonably clear disclosure of the amendments introduced after acceptance. The key contentious amendments and their basis in the specification as filed are summarised as follows:
Amendment
Basis in specification as filed (for example)
Limitation to ‘L adjacent to X is –CH(R10)- where R10 is substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aralkyl’ in claims 1, 6, 8, 27, 33, 50 and dependent claims therefrom
L … represents –(CH2)n-alkyl-, (CH2)n-alkenyl, n is 0 to 5, [page 13, line 20 – page 14 line 17]
By dictionary, ‘alkyl’ refers to the radical of saturated aliphatic groups, including straight chain, branched chain, cycloalkyl, alkyl-substituted cycloalkyl, cycloalkyl-substituted alkyl all of which may be substituted, including with aralkyl [page 30, paragraphs 2 and 3]
Limitation to ‘X is –N(R12)-, where R12 is substituted or unsubstituted lower alkyl’ in claims 1, 6, 8, 27, 33, 50 and dependent claims therefrom
X…selected from –N(R8)-, where R8 may be lower alkyl (up to 10 carbon atoms) [page 14, lines 3 and 4]
By dictionary, ‘alkyl’ refers to the radical of saturated aliphatic groups, including straight chain, branched chain, cycloalkyl, alkyl-substituted cycloalkyl, cycloalkyl-substituted alkyl all of which may be substituted, including with aralkyl [page 30, paragraphs 2 and 3]
Insertion of new definition for ‘L adjacent to R1 and L adjacent to R2’ in compound claim 50 and addition of optional substitutions for L
L … independently for each occurrence represents…[claim 30]
By dictionary, ‘alkyl’ refers to the radical of saturated aliphatic groups, including straight chain, branched chain, cycloalkyl, alkyl-substituted cycloalkyl, cycloalkyl-substituted alkyl all of which may be substituted, including with aralkyl [page 30, paragraphs 2 and 3]
W is narrower in the compound claims (i.e. substituted or unsubstituted benzene ring fixed to the pyrimidine ring)
W represents a substituted or unsubstituted aryl or heteroaryl ring fused to the pyrimidine ring
It is clear that the added provisos and limitations relating to Formula II are in substance disclosed. It follows that with regard to these features the priority date of the claims as proposed to be amended remains that of the date of filing of the specification at the very latest.
However, for similar reasons to those explained under fair basis, no real and reasonable disclosure of general methods for treating cancer and unwanted hair growth can be found in the priority documents or the specification as filed. The first disclosure of matter relating to non-hedgehog pathway treatments is found in the amendments of 16 September 2004, being the addition of consistory clauses and matching claims. Consequently claims 6-9, 11-23, 27, 28, 30-45, 68 and 69 are accorded a priority date of 16 September 2004 with respect to these method/use features only. I will further elaborate on this below.
Novelty
The novelty documents pressed in this Opposition are:
·Compound library available from ComGenex, Inc. on or before 1 October 1998 provided as Exhibit WJP-2
·WO 2001/19800 published 17 April 2001 (the present opposed application)
·WO 2001/16114 published 8 March 2001, priority date 27 August 1999 (ChemoCentryx, Inc.)
I think it useful to point out that with the exception of the Lucas declaration, the vast majority of the opponent’s evidence relating to novelty of the claims was adduced prior to their amendment during the opposition process. While I have given due regard to the evidence much of it has become redundant. Nonetheless the novelty of the claims can be determined by simple comparison of the disclosed compounds to those of the claims.
The law on novelty
The basic test for novelty is the “reverse infringement” test as stated in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd, (1972) RPC 457 at pages 485, 486:
“If carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's patent were valid, would constitute an infringement of the patentee's claim”.
In applying this test regard must be given to the level of disclosure in the prior publication. As stated in Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR at 517:
“It is well accepted that the prior art must disclose all features of the invention embodied in the patent in suit and must do so in clear, unequivocal and unmistakeable terms. The prior art must enable the notionally skilled addressee at once to perceive and understand and be able practically to apply the discovery without the necessity of making further experiments. Whatever is essential to the invention must be read out of or gleaned from the prior publication.”
In Nicaro Holdings, Gummow J also referred to the speech of Lord Reid in C. Van Der Lely N.V. v Bamfords Limited (1963) RPC 61 and 71-72 where Lord Reid reaffirmed the principle set down by Lord Westbury in Hills v Evans [1862] 4 De G, F & J 288; 45 ER 1195 in relation to the level of disclosure necessary to anticipate a claimed invention:
"a person of ordinary knowledge of the subject would at once perceive and understand and be able practically to apply the discovery without the necessity of making further experiments".
Compound library available from ComGenex, Inc
Cytokinetics submit that claims 50-63, 67, 71 and 73-75 lack novelty in light of a library of compounds purchased from Comgenex that were publicly available at the priority date.
Curis submits that the ComGenex library does not constitute a prior art disclosure because there is no evidence that it was publicly available before the priority date, 1 October 1998. This is a key consideration in the present opposition and I must determine whether this library is available under s7(1) of the Act before I can assess the novelty of the claims.
Cytokinetics attests the principle piece of evidence relating to this library is ‘Finer 2’. Dr Finer is employed by Cytokinetics. The relevant parts of his declaration are extracted as follows:
‘In 1998, Chris Shumate, a co-employee of Cytokinetics, Inc., and I asked ComGenex, Inc. to send us details of its small molecule libraries for lead compound screening. In response, ComGenex sent us its catalogue of the compounds included in its libraries. The freely available catalogue was supplied on a searchable CD and without any restrictions on its use.
We reviewed and selected compounds from ComGenex’s catalogue and ordered -23,000 compounds for Cytokinetics screening program. Chris Shumate co-ordinated the purchase. A copy of ComGenex’s invoice dated October 1, 1998 (annexe 2) shows Cytokinetics’ purchase of these compounds.
Comgenex provided a database of the structures and identification numbers of the compounds purchased and this was uploaded to Cytokinetics’ internal database in December 1998. Cytokinetics’ internal database has fields for compound ID numbers, the compound supplier, and the date which the compounds were uploaded to the database. The compound ID numbers correspond to structure types. Therefore, I have been able to print out the -3,400 ComGenex compounds which were uploaded in December 1998 to the internal database and which have a quinazolinone structure. This printout is attached as annexe 3.
Cytokinetics did not buy these compounds to benefit from ComGenex’s synthetic expertise, but rather as a convenient means for assaying a large number of target compounds without the burden of an involved synthetic program. Indeed, the structures of the compounds are not synthetically challenging and their synthesis would have been well within the capability of a synthetic chemist in 1998.’
The invoice annexed to the declaration is indeed dated 1 October 1998 and confirms the purchase of 23 000 1 mg samples of molecular organic compounds by Cytokinetics. The printout of approximately 3 400 compounds provides an identification number and structure but does not contain any dates. The prefix ‘CGX-’ in the identification numbers would appear to confirm the compounds were obtained from Comgenex.
The only evidence led by Curis is the Buckwalter declaration. Dr Buckwalter is a patent agent at Genentech (California, USA) and has extensive experience as a medicinal chemistry researcher. His declaration includes observations that the ComGenex invoice does not directly relate to the list of compounds attached to it and that ‘I see no evidence that supports Finer’s statement that the ‘Comgenex catalogue’ of compounds was freely available or indeed that it was publicly available in October 1998’. He further states that ‘such direct evidence would have been provided to support Finer’s comments.’
As stated above the onus of proof rests with the opponent to clearly establish its case in reaching a conclusion on any issue. However, this is not the case when establishing if a document has been published prior to the priority date. As submitted by the opponent, for determining if a document fulfils the requirements of s7(1), the balance-of-probabilities standard applies. In Austal Ships Pty Ltd v Stena Rederi Aktiebolag [2005] FCA 805 at [12], Bennett J notes
‘I can accept that a lower standard may apply to proof of evidence such as whether a document has been published or, indeed, whether a prior art vessel was well-known. I do not accept that it properly applies to the factual question that itself is the test for obviousness or lack of inventive step. Where the factual question is itself the legal test, as set out in s7(3) of the Act, it seems to me that it should be determined at the higher standard.’
I agree that Cytokinetics would have a much stronger case if the invoice provided more information, the printout provided dates and the CD supplied by ComGenex were in evidence. However, they have nonetheless provided a Statutory Declaration that supports their claim that the library was available before the priority date. Curis on the other hand have only provided a declaration in which a party totally unrelated to the acquisition of the compounds speculates on the evidence before him. I find the Buckwalter declaration of little probative value. I appreciate the submission from Curis that the Commissioner must exercise great caution in an instance such as this. However, in the absence of any controverting evidence, I find that on the balance of probabilities the ComGenex library forms part of the prior art base for the purposes of s7(1).
Having established the public availability of the ComGenex library it is a simple exercise to assess the novelty of the claims. The Lucas declaration identifies 3 compounds from the ComGenex library printout as falling within the scope of the claims. On inspection I agree with Lucas and the submissions made by Cytokinetics at the hearing in that at least compounds CGX-0353865, CGX-0430485 and CGX-0433189 fall squarely within the scope of claims 50-63, 71 and 73-75. This matter of fact was not disputed by the applicant. In addition to these compounds Lucas has provided a list disclosing some 3 461 compounds ‘which also appear to fall within the scope of at least claim 50’. No further information is submitted by Cytokinetics regarding these compounds. At the hearing, when asked about the content of this extensive list, the opponent stated that it would not be necessary for the Hearing Officer to look to the list for compounds anticipating any other claims than those already contested. The applicant has however been put on notice that some of these compounds may be prejudicial to the novelty of any subsequently amended claims.
Claim 67 defines a sterile pharmaceutical excipient and the compound of any one of claims 50-66. The citation does not disclose any pharmaceutical excipients whatsoever and does not teach the compounds to be useful as pharmaceuticals. Claim 67 is novel in light of this document.
I find that claims 50-63, 71 and 73-75 are not novel in light of this document.
WO 2001/19800
At the hearing Cytokinetics advanced the curious proposition that the opposed application itself anticipates the amended claims. Their argument may be broken down as follows;
·As a result of amendment claims 6-9, 11-23, 27, 28, 30-45, 68 and 69 are broader in scope and include methods/uses directed to generally treating cancer and unwanted hair growth that may not be attributed to hedgehog signalling pathway activation
·The claims include matter that was not in substance disclosed in the specification as filed
·According to s114 and Regulation 3.14 (cited above) the priority date of the amended claims takes that of their filing date, being 16 September 2004
·The specification as filed discloses methods/uses directed to treating cancer and unwanted hair growth that is attributed to hedgehog signalling pathway activation
·Methods/uses for treating hedgehog pathway activation related cancer or unwanted hair growth falls within the scope of claims to methods/uses for treating any cancer or unwanted hair growth and therefore deprives them of novelty
I agree that claims 6-9, 11-23, 27, 28, 30-45, 68 and 69 are based on matter that was not in substance disclosed in the specification as filed. However, the specification still cannot anticipate these claims.
S.43(3) provides
(3) Where a claim defines more than one form of an invention, then, for the purposes of determining the priority date of the claim, it must be treated as if it were a separate claim for each form of the invention that is defined.
In this case the claims define two forms of invention and are accordingly treated as separate claims. They may be notionally divided into methods/uses related to treatment of
(a)hedgehog signalling pathway activated cancer/unwanted hair growth taking the priority date of the filed specification at the latest, being 15 September 2000
(b)all other cancer/unwanted hair growth (being non-hedgehog signalling pathway activated) taking a priority date according to Regulation 3.14(b), being 16 September 2004
It follows that in relation to (a) the opposed application as filed does not form part of the prior art base, and in relation to (b) the opposed application as filed cannot possibly provide clear and unmistakable directions given the claims define matter that is not in substance disclosed in the specification as filed.
It follows that claims 1-76 are novel in light of this document. To find otherwise would be absurd.
WO 2001/16114
It is submitted that this document anticipates claims 50, 51, 53-56, 59-62 and 67. This document was published 8 March 2001, after the priority date of compound claims 50 (and appended claims 51, 53-56, 59-62 and 67) however claims priority from US 60/151212 dated 27 August 1999. The document is particularized in the SGP and referred to in the Wentrup, Denny and Lucas declarations. The document is known colloquially as a ‘whole of contents’ document and is considered to form part of the prior art base according to Schedule 1, (b)(ii) relevantly extracted as follows:
prior art base means:
(b) in relation to deciding whether an invention is or is not novel:
(ii) information contained in a published specification filed in respect of a complete application where:
(A) if the information is, or were to be, the subject of a claim of the specification, the claim has, or would have, a priority date earlier than that of the claim under consideration; and
(B) the specification was published after the priority date of the claim under consideration; and
(C) the information was contained in the specification on its filing date and when it was published;
On inspection of US 60/1511212, the claimed priority of WO2001/16114 is valid. The document discloses compounds according to General Formula II that clearly fall within the scope of claims 50, 51, 53-56 and 59-62. Four (4) relevant compounds are found on page 12 and are extracted as follows
The remaining compound is found Table 1, as compound 1.8 which has a general formula of
where R1 is branched nonanoyl, -Y-Z is –(CH2)2N(CH3)2- and Ar is (CH2)2N(CH3)2.
Since the document is directed to pharmaceutical compositions containing these compounds composition claim 67 is also anticipated.
Claims 50, 51, 53-56, 59-62 and 67 are not novel in light of this document.
Inventive step
The law on inventive step
The test for obviousness is whether it would have been a matter of routine to proceed to the claimed invention.
“The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not.” (Aicken J in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12 at [45]; (1981) 148 CLR 262 at 286)
More recently, the High Court in Aktiebolaget Hassle v Alphapharm Pty Ltd [2002] HCA 59 at [53]; 212 CLR 411 at [53] approved the approach taken in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at 187 in which Graham J had posed the question:
“Would the notional research group at the relevant date in all the circumstances directly be led as a matter of course to try [the claimed invention] in the expectation that it might well produce a useful, desired result?”
Is the invention obvious?
The Opponent contends that the claims of the present application are devoid of an inventive step when considered under s7(3), being that the invention as claimed is obvious when the common general knowledge of the person skilled in the art at the earliest priority date is considered together with either
- US 5 756 502 published 26 May 1998 (Warner-Lambert Co) (claims 1-48)
- the ComGenex library cited above (claims 50-63, 71, 73-75)
The problem is determined from the specification. The problem is to provide methods and reagents for inhibiting aberrant growth states resulting from activation of the hedgehog signalling pathway. The person skilled in the art would be a medicinal chemist.
US 5 756 502
The citation discloses quinazolinone derivatives and their use as cholyecystokinin (CCK) ligands in pharmaceutical compositions for suppressing appetite and reducing acid secretion. The compounds do not fall within the scope of any of claims 1-48 following amendment. I note that in discussion of the background art, it is briefly suggested that antagonists of CCK/gastrin receptors could be of therapeutic value as antitumor agents [column 2, lines 10-25]. No mention is made of the hedgehog signalling pathway.
Cytokinetics submit that the invention as defined in claims 1-48 is obvious in light of this document combined with the common general knowledge at the priority date of the claims. For this argument to succeed it must be clearly established that given the problem, the skilled artisan could reasonably be expected to have ascertained, understood and regarded the document as relevant. It must further be shown that if the information contained in the document had been considered by the hypothetical skilled addressee together with the common general knowledge at the relevant time, the invention would have been obvious.
Williams [1.9] and Wentrup [1.6] declare that they often refer to patent documents when identified by databases such as Chemical Abstracts and SciFinder. This is the only evidence led in relation to ascertaining, understanding and regarding the document as relevant. Most importantly, with the exception of the very limited background evidence contained in Rothnagel No 2, no evidence has been adduced that identifies the problem, no evidence has been adduced that establishes the common general knowledge at the priority date and no evidence has been adduced that goes to whether the skilled addressee, given the document, would be directly led to the invention. The onus of proof lies squarely with the opponent and is a matter of evidence (particularly in relation to obviousness).
I am not convinced a sufficient case has been made to support an allegation of lack of inventive step against claims 1-76.
The ComGenex Library
As discussed under novelty above, the ComGenex library teaches the compounds of claims 50-63, 71 and 73-75. While it may be tempting to assume a claim that lacks novelty also lacks inventive step this is not necessarily the case. Inventive step is determined on its own merits.
Cytokinetics submit that the claims lack an inventive step in light of this document combined with the common general knowledge at the priority date of the claims. Again, for this argument to succeed it must be clearly established that given the problem, the skilled artisan could reasonably be expected to have ascertained, understood and regarded the document as relevant. It must further be shown that if the information contained in the document had been considered by the hypothetical skilled addressee together with the common general knowledge at the relevant time, the invention would have been obvious.
I have no evidence before me in relation in relation to ascertaining, understanding and regarding the document as relevant. (In any case, given the obscurity of the document I find it highly unlikely that the skilled artisan would ascertain or find the document to be of relevance.) Furthermore, no evidence has been adduced that identifies the problem, establishes the common general knowledge at the priority date or that goes to whether the skilled addressee, given the document, would be directly led to the invention. In any event, considering the document contains no indication of the activity of the compounds it is difficult to imagine how a skilled artisan would be directly led to the claimed invention. Given that the onus of proof in relation to obviousness lies squarely with the opponent and is a matter of evidence, I am again not convinced a sufficient case has been made to support an allegation of lack of inventive step.
It has not been established that claims 1-76 are not inventive in light of this document.
Manner of Manufacture
Section 18(1)(a) requires that an invention must be a manner of manufacture within the meaning of section 6 of the Statute of Monopolies. Manner of manufacture is assessed by asking whether the claimed invention lacks the necessary quality of inventiveness on the face of the specification (NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1995] HCA 15 at [9]; (1995) 183 CLR 655 at 655).
In their SGP the opponent argued that the alleged invention of claim 1 is that of the mere administration of a known compound to cells to which the compound is known to be administered. While the matter was not pursued at the hearing I nevertheless note that this contention is not apparent on the face of the specification. Any reasoning simply restating the opponent’s novelty and inventive step arguments has been fully considered under those grounds and I do not propose to revisit them under a different one.
Clarity
The opponent contends that claim 50 is not clear. The Lucas declaration provides
‘Variable Z is defined as ‘-N(R8)-, -O-, -S-, a heterocyclic group, or a direct bond between Y and L. The definition of ‘R8’ in claim 50 includes the phrases ‘independently for each occurrence’ and ‘or two R8 groups taken together may form a 4- to 8- membered ring, together with the atoms to which they are attached, which ring may include one or more carbonyls;’.
The applicant has not provided any evidence that controverts the Lucas declaration. I agree that with regard to R8, on the face of the claim it is not clear what is contemplated by variable Z. By reference to the description, I find two possible definitions wherein Z can contain either a single R8 group or two R8 groups which may include a ring. This casts doubt on the scope of the claim.
I find that claim 50 is not clear.
Utility
When assessing utility, the test to be applied is:
‘to judge of utility the directions in the specification must be followed, and if the result is that the object sought to be obtained can be attained, and is practically useful at the time when the patent is granted, the test of utility is satisfied … ‘Useful for what?’ is a question which must always be asked, and the answer must be useful for the purposes indicated by the patentee’ (Lane Fox v Kensington & Knightsbridge Electric Lighting Co (1892) 9 RPC 411 at 417)
More recently, the issue of utility was considered by the Full Court of the Federal Court, which held that:
‘A claim is bad if it covers means that will not produce the desired result, even if a skilled person would know which means to avoid. That is to say, everything that is within the scope of a claim must be useful, otherwise the claim will fail for inutility’ (Emmett J in H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70 at [81]; (2009) 81 IPR 228 at 247 [81]).
Therefore, it follows that lack of utility is established when a claim includes subject matter that will not produce the desired result. In this case the desired result is to either treat cancer or unwanted hair growth.
The opponent alleges that claims 6-9, 11-23, 27, 28, 30-45 and omnibus claims 68 and 69 are not useful because compounds within the scope of the claims have been shown to be ineffective in inhibiting the proliferation of human ovarian cancer cells (SKOV3) [Rothnagel No 2 and Finer 1]
In response, Curis rely on the Sauvage declaration which concludes that the results obtained by Dr Finer from testing compounds in an assay does not establish that the compound would be inactive in vivo because there is a basic flaw in the assay [1.6]. Sauvage explains that since hedgehog signalling is a paracrine mechanism and not a cell-autonomous mechanism small molecule inhibitors would not exhibit an effect on viability of isolated cancer cell lines in vitro regardless of hedgehog expression [2.3]. In my view Curis have provided sufficient evidence to explain the results of the Finer experiments.
It follows that inutility has not been established for claims 1-76.
CONCLUSION
The opposition succeeds. I find that claims 50-63, 67, 71 and 73-75 are not novel, claim 50 is not clear and claims 6-9, 11-23, 27, 28, 30-45, 68 and 69 are not fairly based.
These are matters that may be overcome by amendment. As there is clearly patentable subject matter within the specification I allow the applicant 60 days from the date of this decision in which to file proposed amendments overcoming the problems noted above.
COSTS
The opposition has succeeded on the grounds of novelty, fair basis and clarity. It is usual practice for costs to follow the event. In this case I see no reason to deviate from this approach. Accordingly I award costs against the applicant, Curis Inc., according to Schedule 8 of the Patent Regulations 1991.
Nicole Howard
Delegate of the Commissioner of Patents
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