Rozenberg & Co Pty Ltd v Seattle Children's Hospital d/b/a Seattle Children's Research Institute
[2023] APO 55
•1 November 2023
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Rozenberg & Co Pty Ltd v Seattle Children's Hospital d/b/a Seattle Children's Research Institute; Fred Hutchinson Cancer Center [2023] APO 55
Patent Application: 2018204209
Title:Method and compositions for cellular immunotherapy
Patent Applicant: Seattle Children's Hospital d/b/a Seattle Children's Research Institute; Fred Hutchinson Cancer Center
Opponent:Rozenberg & Co Pty Ltd
Delegate:M. Umehara
Decision Date: 1 November 2023
Hearing Date: 16 August 2023, in Canberra
Catchwords: PATENTS – opposition to the grant of a patent under s59 – claim construction – clarity – claims define the invention – clear enough and complete enough disclosure – the specification provides sufficient information – best method – support – manner of manufacture – utility – “whole of contents” novelty – inventive step –none of the grounds have been made out – opposition unsuccessful – costs awarded against the opponent
Representation: Counsel for the applicant: Craig Smith
Patent attorney for the applicant: Karen Bentley and Thomas Ware of FPA Patent Attorneys
Counsel for the opponent: Katrina Howard
Patent attorney for the opponent: Danielle Burns and David Longmuir of Phillips Ormonde Fitzpatrick
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2018204209
Title:Method and compositions for cellular immunotherapy
Patent Applicant: Seattle Children's Hospital d/b/a Seattle Children's Research Institute; Fred Hutchinson Cancer Center
Date of Decision: 1 November 2023
DECISION
The opposition is unsuccessful. Subject to appeal, I direct the application proceed to grant.
I award costs according to Schedule 8 against the opponent, Rozenberg & Co Pty Ltd.
REASONS FOR DECISION
Background
Patent application 2018204209 (the application) was filed by Seattle Children's Hospital d/b/a Seattle Children's Research Institute and Fred Hutchinson Cancer Center (together, the applicant) on 13 June 2018 as a divisional application of application 2013305838 (the parent application). The parent application was filed on 20 August 2013 under the provisions of the PCT and claiming priority from US 61/691,117 (the priority document) which was filed on 20 August 2012.
Acceptance of the application was advertised on 15 October 2020. Rozenberg & Co Pty Ltd (the opponent) filed a notice of opposition under section 59 of the Patents Act 1990 (the Act) on 15 January 2021.
A statement of grounds and particulars (SGP) was filed on 15 April 2021, identifying the following grounds of opposition: manner of manufacture, novelty, inventive step, utility, sufficiency, best method, claims defining the invention, clarity and succinctness of claims, and support. At the hearing, all grounds, except succinctness of claims, were pressed.
During the period for evidence in answer, the applicant proposed post-acceptance amendments to the specification on 2 September 2021. Leave to amend was granted on 6 October 2021, and on 21 December 2021 the opponent opposed the allowance of the amendments. However, on 13 July 2022 the opponent withdrew its opposition to the allowance of the amendments, and the amendments were allowed on 8 August 2022.
Following the completion of the evidentiary rounds, the opponent proposed amendments to the SGP on 7 October 2022. While this amendment was ultimately refused, an alternate amendment to the statement of proposed amendments was proposed and was allowed on 4 January 2023. The opponent nonetheless chose to advance particulars in their submissions that were not allowed into the SGP.[1] This is discussed in detail below.
[1] Opponent submissions [333]-[340].
Evidence
The evidence filed during the evidentiary periods is summarised in the table below:
Evidence Declarant Exhibits/Annexures Declaration Date Reference In Support Michael P. Brown MPB-1 to MPB-23 15 July 2021 Brown #1 Carl DeSelm CDS-1 to CDS-17 13 July 2021 DeSelm Danielle Burns DXB-1 to DXB-5 13 July 2021 Burns In Answer Marcela V. Maus MVM-1 to MVM-16 14 October 2021 Maus In Reply Michael P. Brown MPB-24 to MPB-46 21 December 2021 Brown #2
Onus
Because the application was filed after 15 April 2013, the amendments to the Act brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (the Raising the Bar Act) apply to it. This includes section 60(3A) of the Act, which provides that the Commissioner may refuse an application if satisfied on the balance of probabilities that a ground of opposition to the grant of a patent exists. Nevertheless, it remains the case that, in proceedings such as these before the Commissioner, the onus rests with the opponent to establish its case.
Background to technology
The opposed application is broadly directed to the field of cellular immunotherapy comprising T cells modified with tumour-targeting receptors, better known as chimeric antigen receptors (CARs). It is useful to set out some uncontroversial background information concerning CARs and their use in CAR-T cell therapy.
“Immunotherapy” is a branch of cancer treatment that looks at ways of modifying the immune system to increase the destruction of cancer cells and avoiding cancer cell escapes and includes a range of therapies. Immune checkpoint inhibitors block the built-in mechanism of dampening immune responses so T cells can invoke a stronger response. T cell transfer therapy, or adoptive cell therapy, involves taking T cells from the tumour, selectively boosting the number of those which are most active against the cancer and injecting them back into the patient. Monoclonal antibodies mark cancer cells so that they will be better seen and destroyed by the immune system. Treatment vaccines prime the immune system to boost the immune response to cancer cells. Immune system modulators may enhance the body’s immune response against cancer by affecting specific parts of the immune system or in a general way.
As part of its normal function, the immune system detects and destroys abnormal cells and infectious agents. CAR-T cell therapy takes advantage of T cells’ natural ability to detect and destroy abnormal cells and further directs them towards killing cancer cells by replacing the antigen-binding portion of the T cell receptor with the antigen-binding portion of tumour-specific antibodies:
[2]
[2] Journal of Biomedicine and Biotechnology, 2010, article 956304, Figure 1.
The variable fragment (Fv) is the smallest unit of immunoglobulin (or antibody) molecule with function in antigen-binding activities. An antibody in single chain fragment variable (scFv) format consists of variable regions of heavy (VH) and light (VL) chains, which are joined together by a flexible peptide linker:
[3]
[3] Clinical and Developmental Immunology, vol. 2012, Article ID 980250, Figure 1
In general, a CAR construct comprises four domains:
·an extracellular ligand binding domain, which commonly comprises variable heavy and light chains of an antibody in a scFv format;
·a spacer or hinge region, which connects the extracellular domain to the transmembrane domain;
·a transmembrane domain, which anchors the CAR to the T cell; and
·an intracellular signalling domain, which activates T cell effector functions and usually contains the CD3ζ chain from the T cell receptor complex and may contain additional costimulatory signalling domains.[4]
[4] Brown #1 at [39]-[40].
By employing an appropriate ligand binding domain, CARs can bind to target antigens expressed on the tumour cell surface and cause T cell activation, expansion and tumour cell killing:
[5]
[5] Journal of Biomedicine and Biotechnology, 2010, article 956304, Figure 2; Brown #1 at [36].
The CAR-T cell therapy process involves collecting the patient’s blood, genetically modifying the T cells to express CARs, expanding the population of modified CAR-T cells, and infusing them back into the patient. The CAR is designed to recognise specific antigens that are only present on the surface of cancer cells. Once infused back into the patient, when the CAR-T cells come across the target antigen, they bind and cause the cancer cells expressing the target antigen to be destroyed.
[6]
[6] Opponent submissions, Annexure B, slide 1.
The first true CAR-T cell was produced in 1989, when the variable regions of the heavy and light chains from an antibody were spliced on to the constant domains of the α and β chains of the T cell receptor.[7] CARs were first designed with a single intracellular signalling domain and successive generations have added co-stimulatory domains to enhance their in vivo activity.[8]
[9]
[7] Maus at [29].
[8] Maus at [26]-[27].
[9] Journal of Biomedicine and Biotechnology, 2010, article 956304, Figure 3.
It is important to note that a CAR is not a drug that is administered to a patient as such. A nucleic acid encoding the modular components is inserted into a host cell and the cell itself expresses the CAR. The nucleic acid sequence that encodes the CAR links together a number of modular components for efficient T cell activation and recognition of a specific target molecule. The nucleic acid must also include an expression system to incorporate the CAR into the host cell.
Further developments have been made in the field to add more functions, safety mechanisms and explore alternative binding mechanisms:
[10]
[10] Cancers, 2020, vol. 12, no. 9, article 2360; doi:10.3390/cancers12092360, Figure 1.
Of relevance to the present matter, a tandem CAR comprises two scFv domains connected via a flexible linker to create a bispecific CAR. The tandem-CAR has greater binding specificity and stronger binding in comparison to a single-scFv CAR. An alternative means for increasing the binding properties of a CAR is to introduce an additional engager component or a peptide bridge. In these constructs, the scFv component does not directly bind to the target and the main CAR construct is universal for all targets as the bispecific antibodies or a tumour-recognisable protein acts as a bridge between the CAR-T cell and the tumour cell.
The person skilled in the art
It is well established that many of the issues in an opposition are answered by reference to the person skilled in the art:
“He is the person to whom the patent is addressed and who must construe it. He is the person whose knowledge will determine whether a patent is novel. He is the person who will judge whether a patent is obvious.”[11]
[11] Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at [70].
The hypothetical skilled person works in the field with which the invention is connected and is a non-inventive person or team likely to have a practical interest in the subject matter of the invention.[12] Where the invention lies in a specific field of the art, the hypothetical skilled person should have practical experience in that specific art, not in broader or related arts.[13] Furthermore, as noted by Nicholas J in ToolGen Incorporated v Fisher (No 2), the notional team for considering obviousness may have wider skills than the team required for sufficiency.[14]
[12] Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at [70]-[72].
[13] Fina Research SA v Halliburton Energy Services Inc. [2003] FCA 55 at [8]-[9].
[14] ToolGen Incorporated v Fisher (No 2) [2023] FCA 794 at [81].
The specification is directed to the field of CARs for carrying out CAR-T cell therapy. Accordingly, the skilled person, or team, would be expected to have a practical interest in the field of CARs, including the development of CAR constructs, transduction into T cells and use in cellular immunotherapy. The skilled person is a highly specialised individual, or a team of individuals, in the field of cancer immunotherapy involved in the design, identification and testing of CAR construct candidates and manufacture of CAR-T cells for clinical use.[15]
[15] Opponent submissions at [25].
The key declarants in this matter are Professor Brown and Dr DeSelm for the opponent and Associate Professor Maus for the applicant. Dr Burns is an attorney acting for the opponent and provided information on the family history of the present application and corporate history for Juno Therapeutics, a licensee of the applicant, and their activity in developing the BREYANZI product.
Professor Brown is the Clinical Professor and Professor of Medical Oncology in the School of Medicine at the University of Adelaide, Director of the Royal Adelaide Hospital Cancer Clinical Trials Unit and the Head of the Translational Oncology Laboratory at the Centre for Cancer Biology.[16] Professor Brown has research experience in the application of immunotherapeutic technologies to the treatment of various cancers and clinical experiences relating to oncology.[17] Professor Brown has been actively researching CAR-T cell technology since 2010.[18]
[16] Brown #1 at [1].
[17] Brown #1 at [2]-[15].
[18] Brown #1 at [3].
Dr DeSelm is an Assistant Professor in the Department of Radiation Oncology and Center for Human Immunology and Immunotherapy Program at Washington University.[19] Dr DeSelm has experience in cancer immunotherapy, clinical treatment of cancer patients and CAR-T cells.[20] After completing his molecular cell biology PhD in 2009 and his MD in 2012, Dr DeSelm was an intern in internal medicine for the period of 2012-2013.[21] Following a residency in radiation oncology, Dr DeSelm completed a research fellowship in CAR-T cell therapy for solid tumours in the period of 2016-2017.[22]
[19] DeSelm at [1].
[20] DeSelm at [2]-[4].
[21] DeSelm at [2]-[3].
[22] DeSelm at [3].
Associate Professor Maus is an Associate Professor of Medicine at Harvard Medical School and the Director of cellular immunotherapy at the Massachusetts General Hospital Cancer Center.[23] Associate Professor Maus has research experience in developing artificial antigen presenting cells, describing cellular functions and characterising immune response to vector proteins as well as clinical training.[24] After completing her T cell activation biology PhD in 2003 and her MD in 2005, Associate Professor Maus was leading a translational medicine and early clinical development team in 2012.[25]
[23] Maus at [1].
[24] Maus at [7]-[14].
[25] Maus at [7] and [12].
At the hearing, there was general agreement that each of the experts had relevant qualifications and experience in varying aspects of the field. For example, although Professor Brown lacks direct experience in designing a CAR,[26] he has reviewed papers and used CARs in immunotherapy such that he would be reasonably familiar with the field.[27] I consider that all key declarants have backgrounds that enable them to understand the specification and provide evidence in relation to what a person skilled in the art knew or would have done at the relevant date. Where there is conflicting evidence, I will decide which evidence should be given greater weight in the usual manner.
[26] Applicant submissions at [102].
[27] Brown #1 at [21], [26], [96].
The specification
The specification includes a sequence listing and ends with 20 figures and 49 claims. Before construing the specification, I note the comments of Middleton J in Eli Lilly and Company Limited v Apotex Pty Ltd:
“It is well settled that the Court should, from the outset, approach the task of patent construction with a generous measure of common sense. The Court must place itself in the position of a person skilled in the relevant art, being the subject matter of the patent. From this perspective, the patent is to be read as a whole, in the context of the specification and in light of the prevailing common general knowledge and state of the relevant art at the priority date.” [28]
The invention as described
[28] Eli Lilly and Company Limited v Apotex Pty Ltd [2013] FCA 214; 100 IPR 451 at [139].
The invention described in the opposed application relates to the field of cancer immunotherapy comprising T cells modified with tumour antigen receptors.[29] The specification sets out the background to CAR constructs and CAR-T cell therapy, which are consistent with the discussion of the technology background provided above.
[29] Specification at page 1 lines 6-8.
The specification then goes on to laying out the discovery that set the course for the inventors:
“It has been surprisingly found that the length of the spacer region that is presumed not to have signaling capability affects the in vivo efficacy of the T cells modified to express the chimeric receptor and needs to be customized for individual target molecules for optimal tumor or target cell recognition.”[30]
[30] Specification at page 2 lines 27-31.
That is, in comparison to a reference CAR, the spacer-customised CAR provides for enhanced T cell proliferation and/or cytokine production.[31] A plasmid library of DNA sequences that encode extracellular components including the hinge of the IgG4 hinger alone, IgG4 hinge linked to CH2 and CH3 domains, or IgG4 hinge linked to the CH3 domain, linked to a CD28 transmembrane and intracellular signalling domains, a T2A self-cleaving sequence and a selectable marker encoding a truncated human epidermal growth factor was generated.[32] Any scFv sequence can be attached to the sequences encoding this library of variable spacer domains.[33]
[31] Specification at page 4 lines 3-6.
[32] Specification at page 6 lines 5-8.
[33] Specification at page 6 lines 8-9.
An approach for conducting the relevant study for customising the spacer is then described:
“In embodiments, a library of nucleic acids is provided, wherein each nucleic acid codes for a spacer region that differs from the others in sequence and length. Each of the nucleic acids can then be used to form a chimeric receptor nucleic acid construct that can be tested in vivo (in an animal model) and/or in vitro so that a spacer can be selected that provides for improved tumor recognition, increased T cell proliferation and/or cytokine production in response to the ligand.”[34]
[34] Specification at page 22 line 31 – page 23 line 4.
This allows for the design of a CAR customised for the type of tumour, the target antigen present on the tumour, the affinity of the antigen-binding domain for the target antigen, the flexibility needed for the antigen-binding domain, and/or the intracellular signalling domain.[35] The target antigen may be selected based on the characterisation of the cell-surface antigens present on a subject’s tumour cell, which is predominantly found on the tumour cells and not found on normal tissues.[36] When the target antigen is located proximal to the membrane of the target cell, a longer spacer may be selected, and when the target antigen is located distal to the membrane of the target cell, a short spacer may be selected.[37]
[35] Specification at page 23 lines 14-17.
[36] Specification at page 23 lines 27-33.
[37] Specification at page 24 lines 12-24.
For the present invention, a library of polynucleotides coding for various spacer regions is provided and the selection process promotes optimal tumour cell recognition based on the epitope location, affinity of the antibody for the antigen and/or the general ability of the T cells expressing the CAR to proliferate in response to antigen recognition.[38] Using a library of polynucleotides, each coding for different spacer components, a method of selecting a spacer region for a CAR is provided:
“In embodiments, a method comprises providing a plurality of chimeric receptor nucleic acids, wherein the chimeric receptor nucleic acids differ only in the spacer region; introducing each of the chimeric receptor nucleic acids into a separate T lymphocyte population; expanding each separate lymphocyte population in vitro, and in1l'oducing each lymphocyte population into an animal bearing a tumor to determine the anti-tumor efficacy of each of the chimeric receptors when expressed in T cells, and selecting a chimeric receptor that provides anti-tumor efficacy as compared to each of the other separate lymphocyte populations modified with each of the other chimeric receptors.”[39]
[38] Specification at page 31 lines 20-30.
[39] Specification at page 34 lines 10-18.
The specification concludes with three worked examples illustrating the concept of how spacer selection benefits by preparing CARs directed to ROR1, Her2 and CD19 with varying spacer components. Of particular relevance to the present matter is Example 3:
“CD19 specific chimeric receptors were constructed using: (1) the VL and VH chain segments of the CD19-specific mAb FMC63 (SEQ ID NO:3), linked by a (G4S)3 linker (SEQ ID NO:12) peptide (VL-linker-VH); (2) a spacer domain derived from IgG4-Fc (Uniprot Database: P01861, (SEQ ID NO:13)) comprising either the Hinge-CH2-CH3 portion (229 AA, (SEQ ID NO:) [sic]) or Hinge only (12 AA; (SEQ ID NO:4)). Both spacers contained a S → P substitution within the Hinge domain located at position 108 of the native IgG4-Fc protein; the 27 AA transmembrane domain of human CD28 (Uniprot Database: P10747, (SEQ ID NO:14)); (4) a signaling module comprising either (i) the 41 AA cytoplasmic domain of human CD28 with an LL → GG substitution located at position 186-187 of the native CD28 protein (SEQ ID NO:14); and/or (ii) the 42 AA cytoplasmic domain of human 4-1BB (Uniprot Database: Q07011, (SEQ ID NO:15)); linked to (iii) the 112 AA cytoplasmic domain of isoform 3 of human CD3ζ; (Uniprot Database: P20963, (SEQ ID NO:16)); the self cleaving T2A sequence (SEQ ID NO:8); and (6) a truncated epidermal growth factor receptor (EGFR) sequence (SEQ ID NO:9).”[40]
[40] Specification at page 72 lines 10-24.
The nucleotide sequences encoding each component were synthesised and cloned into a lentiviral vector.[41] The vector was introduced into purified T cells, which were then expanded in culture.[42] The modified T cells were dosed into tumour-bearing mice.[43] The following observation was made:
“Surprisingly, only T cells modified to express CD19 chimeric receptors with short extracellular spacer domain ('short/CD28' and 'short/4-1BB') eradicated Raji tumors in this model, whereas mice treated with T cells expressing CD19 chimeric receptors with long spacer ('long/CD28' and 'long/4-1BB') developed systemic lymphoma and hind limb paralysis with nearly identical kinetics as untreated mice or mice treated with control tEGFR+ T cells (Figure 15B, C). The striking difference in antitumor activity between CD19 chimeric receptors with short and long spacer domains was highly significant and reproducible in multiple experiments with chimeric receptor T cell lines generated from 3 different normal donors.”[44]
[41] Specification at page 72 lines 25-29.
[42] Specification at page 75 lines 7-12.
[43] Specification page 76 line 30 – page 77 line 6.
[44] Specification at page 77 lines 7-15.
Based on these additional experiments, the conclusion was that the length of the spacer was a decisive element for the in vivo anti-tumour activity for the CD19-CAR.[45] That is, for a CAR construct comprising a scFv derived from the CD19-specific monoclonal antibody FMC63, which is reflected in the amino acid sequence encoded by SEQ ID NO:3, the short IgG4 hinge spacer of amino acid sequence encoded by SEQ ID NO:21 was critical in conferring the potent anti-tumour reactivity. The long IgG4 hinge-CH2-CH3 spacer did not have the same effect and altering the costimulatory region did not alter the anti-tumour reactivity.
The claims
[45] Specification at page 82 lines 8-15.
The correct approach to the construction of claims was discussed by Bennett J in H Lundbeck A/S v Alphapharm Pty Ltd:
“the words in a claim should be read through the eyes of the skilled addressee in the context in which they appear. … While the claims define the monopoly claimed in the words of the patentee’s choosing, the specification should be read as a whole … It is not permissible to read into a claim an additional integer or limitation to vary or qualify the claim by reference to the body of the specification … terms in the claim which are unclear may be defined or clarified by reference to the body of the specification.” [46]
[46] H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70; 81 IPR 228 at [118]-[120].
The claims are to be construed in light of the specification as a whole, but the plain and unambiguous meaning of a claim cannot be varied or qualified by reference to the body of the specification.[47] Further, a construction according to which the invention will work is to be preferred to one in which it may not.[48]
[47] Welch Perrin & Co Pty Ltd v Worrel [1961] HCA 91; (1961) 106 CLR 588 at [610].
[48] Pfizer Overseas Pharmaceuticals v Eli Lilly & Company [2005] FCAFC 224; (2005) 225 ALR 416 at [250].
The Full Court in Airco Fasteners Pty Ltd v Illinois Tool Works Inc.,[49] recently reiterated the principle that experts can give evidence on the meaning which those skilled in the art would give to technical or scientific terms and phrases and on any unusual or special meanings that would be given by skilled addressees to words which might otherwise bear their ordinary meaning,[50] and the Court is to place itself in the position of some person acquainted with the surrounding circumstances as to the state of the art and manufacture at the time.[51] However, it is for the Court, not for any witness however expert, to construe the specification.[52] A similar approach is taken in matters before the Commissioner.
[49] Airco Fasteners Pty Ltd v Illinois Tool Works Inc. [2023] FCAFC 7 at [48].
[50] Sartas No 1 Pty Ltd v Koukourou & Partners Pty Ltd [1994] FCA 1529; 30 IPR 479 at [485]- [486].
[51] Kimberley-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8; 207 CLR 1 at [24].
[52] Sartas No 1 Pty Ltd v Koukourou & Partners Pty Ltd [1994] FCA 1529; 30 IPR 479at [485]-[486].
The entire claim set is reproduced at Annex A. Claims 1, 2, 22, 23, 25 and 33 are independent. Claims 1 and 2, directed to nucleic acids encoding a chimeric receptor, are reproduced below as they represent the broadest embodiments of the claimed invention. Claims 22 and 23 define chimeric receptor polypeptide in terms corresponding to claims 1 and 2, respectively. Claims 25 and 33 define the CAR expression machinery in nucleic acid and amino acid forms, respectively, comprising a leader sequence, the anti-CD19 scFv domain, short IgG4 hinge spacer, CD28 transmembrane domain, 41BB co-stimulatory domain, CD3ζ signalling domain, T2A self-cleaving domain, and an EGFRt marker domain.
1. A nucleic acid encoding a chimeric receptor, the chimeric receptor comprising an extracellular domain consisting of a single chain variable fragment (scFv) and an extracellular polypeptide spacer, a transmembrane domain and an intracellular signaling domain, wherein:
(a)the scFv binds to a CD19 and comprises a variable light chain (VL) domain comprising a CDRL1, a CDRL2, and a CDRL3 of the amino acid sequence encoded by SEQ ID NO:3, and a variable heavy chain (VH) domain comprising a CDRH1, a CDRH2, and a CDRH3 of the amino acid sequence encoded by SEQ ID NO:3;
(b)the polypeptide spacer is located between the scFv and the transmembrane domain, wherein the polypeptide spacer is 15 amino acids or less in length and comprises the amino acid sequence of SEQ ID NO:21; and
(c)the intracellular signaling domain comprises a CD3ζ signaling domain and a costimulatory domain.
2. A nucleic acid encoding a chimeric receptor, the nucleic acid comprising:
(a)a polynucleotide encoding a single chain variable fragment (scFv) that binds to CD19, wherein the scFv comprises:
a variable light chain (VL) domain comprising a VL domain present in the amino acid sequence encoded by SEQ ID NO:3, and a variable heavy chain (VH) domain comprising a VH domain present in the amino acid sequence encoded by SEQ ID NO:3; or the amino acid sequence encoded by SEQ ID NO:3;
(b)a polynucleotide encoding a transmembrane domain;
(c)a polynucleotide encoding a polypeptide spacer located between the scFv and the transmembrane domain, wherein the polypeptide spacer is 15 amino acids or less in length and comprises the amino acid sequence of SEQ ID NO:21; and
(d)a polynucleotide encoding an intracellular signaling domain that comprises a CD3ζ signaling domain and a costimulatory domain.
Dependent claims 26-32 are directed to an expression vector comprising the nucleic acid of any one of claims 1-20 or a nucleic acid encoding the chimeric receptor polypeptide of any one of claims 21-25. Dependent claims 34-42 are directed to host cells and dependent claims 43-46 are directed to compositions comprising these host cells. Finally, dependent claims 46-49 are directed to the in vitro method for preparing the host cells.
Broad vs narrow
There was no apparent dispute between the experts as to what the claims defined. Professor Brown arrived at an interpretation that the claims were directed to single-scFv CAR constructs and Associate Professor Maus generally agreed with this interpretation.[53] Nothing in evidence suggested potential issues with the breadth of the claimed subject matter.
[53] Brown #1 at [126], [136] and [137]; Maus at [118]; Brown #2 at [53].
However, at the hearing, the opponent advanced the construction of the present claims in two streams: the broad and the narrow. The opponent submitted that construing the claims broadly would allow two or more of each of the components of the CAR constructs to be present, which “would include millions of combinations and millions of CARs, which would be absurd.”[54] The possible inclusion of two or more scFvs within a CAR construct, such as in tandem CARs, by the broad construction was of particular concern to the opponent. In the alternative, the opponent submitted that with a narrow construction, the claims are directed to CARs with a single scFv, a single spacer, a single transmembrane domain, and a single intracellular signalling domain, which would be consistent with the meaning given by the experts. The intracellular signalling domain is a combination of sub-domains including a signalling domain and a costimulatory domain.
[54] Opponent submissions at [69].
As observed by the applicant, the opponent advanced this issue despite the amendments to introduce particulars relating to the broad and narrow constructions into their SGP not being allowed and significance of either construction was not developed in their evidence.[55] I agree with the applicant in that the opponent did not clearly particularise this point in their SGP and no evidence has been adduced by either party on the consequences of either construction. Nevertheless, it is necessary for me to construe the claims.
[55] Applicant submissions at [15].
As set out above, the claims are directed to CARs comprising a scFv, a spacer, a transmembrane domain, and an intracellular signalling domain. The terms “comprising” and “comprises” are often construed as inclusive terms, but they can also be construed as exclusive terms if it is apparent that that is how they were meant in the context of the specification.
While there is no definition for the terms “comprising” or “comprises” provided in the specification, the context of the claims makes it clear that the inclusive meaning is intended. For example, claim 1 refers to the VL and VH domains comprising a CDRL1, CDRL2 and CDRL3 or a CDRH1, CDRH2 and CDRH3, respectively. Moreover, in claims 1 and 2, the spacer is defined as being 15 amino acids or less in length and comprises the amino acid sequence of SEQ ID NO:21. Given that scFvs require the framework regions as well as the CDRs and SEQ ID NO:21 is only 12 amino acids long, the terms “comprising” and “comprises” must be present in the inclusive sense. If the terms “comprising” or “comprises” were not inclusive, then claims 1 and 2 would make little sense.
With respect to the other occurrences of the terms “comprising” and “comprises” in the claims, it is unlikely that the same root word used multiple times in the same claim would be construed to have different meanings.[56] Accordingly, claims 1 and 2 are defined by reference to what the CAR construct under consideration includes, not what it consists of.[57] Consequently, the claims require each of a scFv, a spacer, a transmembrane domain and an intracellular signalling domain to be present in the CAR construct but does not prohibit the addition of other components.
[56] Merck Sharp & Dohme Corporation v Wyeth LLC (No 3) [2020] FCA 1477 at [189].
[57] Merck Sharp & Dohme Corporation v Wyeth LLC (No 3) [2020] FCA 1477 at [180].
The opponent submitted that in addition to the required scFv, spacer, transmembrane domain, and intracellular signalling domain, the claims could include other components not specified in the claims, but the required components cannot be replaced with something else.[58] In their view, for example, a scFv cannot be replaced with another form of a ligand binding domain, such as for a tandem-CAR.[59]
[58] Opponent submissions at [62].
[59] Opponent submissions at [62].
The applicant drew my attention to the specification providing examples of antibody fragments such as Fab, diabodies, linear antibodies, scFv and multi-specific antibodies.[60] In their view, the CAR construct described in the specification is therefore not limited to single-scFv CARs. However, I note that this passage includes scFv as a type of a ligand binding domain rather than describing various forms of scFv. That is, the specification clearly defines an scFv as a specific form of ligand binding domain distinct from other ligand binding domains which comprise an scFv. Insofar as the claims require a scFv to be present, I do not consider that alternative forms of ligand binding domains, such as bispecific fragments for tandem-CARs, fall within the scope of the present claims.
[60] Applicant submissions at [33].
Consequently, I consider that the CAR construct must include a scFv (rather than any other form of a ligand binding domain, such as a bispecific antibody fragment), a spacer, a transmembrane domain, and an intracellular signalling domain. This is consistent with the meaning given by the experts, the worked examples in the specification and the specification as a whole. I note that the addition of other components is not prohibited but should not interfere with the function of the CAR-T cell. For example, leader sequences and self-cleaving markers are additional components which may be added to the construct without affecting the function of the CAR-T cell.
the extracellular domain consisting of a scFv and a spacer
Claim 1, and similarly claim 22, is drafted in terms of a CAR comprising an extracellular domain consisting of a scFv and an extracellular polypeptide spacer. Contrasted with the use of the term “comprising” in other aspects of the claim, the term “consisting of” appears to be a deliberate drafting using an exclusive language. Consequently, the defined extracellular domain must have one scFv and one spacer present, without the addition of any other component in the extracellular domain. The intracellular domain may include other components not specified in the claims.
a spacer located between the scFv and the transmembrane domain
Across the claims, there is a limitation that the spacer is located between the scFv and the transmembrane domain. At the hearing, the applicant explained that the claims specify and require a certain structure for the CARs, where the claimed scFv is immediately adjacent to the spacer, which is in turn immediately adjacent to the transmembrane domain.
This is consistent with the plain meaning of “between”, which is relevantly as follows:
preposition 1. in the space separating (two or more points, objects, etc.).
2. intermediate to, in time, quantity, or degree: between 12 and 1 o'clock; between pink and red.
3. connecting: a link between parts.
4. involving; concerning: war between nations; choice between things.
5. by joint action or possession of: to own land between them.
6. distinguishing one thing from another: he can't tell the difference between butter and margarine.
–adverb 7. in the intervening space or time; in an intermediate position or relation: visits far between.
–phrase 8. between you and me or between ourselves, in confidence.
9. come between, to act as a barrier or obstruction to affection, ambition, etc., between (people): don't let your aunt come between us.[61] The Macquarie Dictionary online, 2023, in between, after one item, event, etc., and before another.[61]
While the word “between” has many uses in the English language, I understand the ordinary meaning is the spacer directly linking the claimed scFv and the transmembrane domain. There is nothing in the specification to indicate that anything other than the plain meaning should be given to the term.
Furthermore, in the context of the invention, this reading of the claim is sensible. The relative spatial orientation for the claimed scFv from the transmembrane domain is maintained across the claims because the claimed spacer must be located between these two components.
the single chain variable fragment (scFv)
As explained in the background section above, a scFv consists of the VL and VH chains which are joined together by a flexible peptide linker. The scFv defined in the present claims must bind to CD19 and comprise at least the complementarity-determining regions (CDRs) of the variable light chain (VL) and variable heavy chain (VH) domains present in the amino acid sequence encoded by SEQ ID NO:3. The full DNA sequence of SEQ ID NO:3 encodes the scFv segment of the CD19-specific murine monoclonal antibody known as FMC63.[62]
[62] Specification at page 31 lines 11-13 and page 72 line 11.
In some claims, such as claim 1, the scFv may comprise the CDRs of SEQ ID NO:3 and otherwise unspecified framework portions of the VL, VH and linker segments. Some claims, such as claim 2, require the VL and VH domains present in the amino acid encoded by SEQ ID NO:3, without limiting the linker domain in the scFv. In other claims, the scFv comprises the full amino acid sequence encoded by SEQ ID NO:3, which specifies the VL domain, the Whitlow’s linker, and the VH domain of the scFv segment of FMC63.
the polypeptide spacer
There was no apparent dispute between the experts as to what was intended by the spacer as defined in the claims. However, as the spacer does play an important role in the present invention, I will discuss its features.
The polypeptide spacer is 15 amino acids or less in length, includes the amino acid sequence of SEQ ID NO:21 (ESKYGPPCPPCP), and must also be located between the scFv and the transmembrane domain. The relevance of the location of the spacer between the scFv and the transmembrane domain has been discussed above.
The amino acid sequence of SEQ ID NO:21 corresponds to a 12-amino acid portion of a mutated hinge region of human IgG4.[63] This peptide has a specific mutation from the human IgG4 hinge core from CPSP to CPPC.[64] The native IgG4 hinge suffers from undesirable intra-chain disulfide bond formation which is abrogated by the mutation.[65] The spacer must include the 12 amino acids of encoded by the amino acid sequence of SEQ ID NO:21 but may include up to three more flanking amino acids.
[63] Specification at page 32 lines 29-31.
[64] Specification at page 33 lines 1-3.
[65] Brown #1 at [59]-[60].
Clarity
It is a requirement of subsection 40(3) of the Act that the claims be clear. This requirement is satisfied if a person could ascertain “whether or not what he proposes to do falls within the ambit of the claim”.[66] However, the terms used in claims need not be precise and absolute, as set out in Flexible Steel Lacing Company v Beltreco Ltd:
“Lack of precise definition in claims is not fatal to their validity, so long as they provide a workable standard suitable to the intended use. The consideration is whether, on any reasonable view, the claim has meaning. In determining this, the expressions in question must be understood in a practical, commonsense manner. Absurd constructions should be avoided and mere technicalities should not defeat the grant of protection.” [67]
[66] Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59 at 60.
[67] Flexible Steel Lacing Company v Beltreco Ltd [2000] FCA 890; (2001) 49 IPR 331 at [81] (cited with approval in Austal Ships Sales Pty Ltd v Stena Rederi Aktiebolag [2008] FCAFC 121; (2008) 77 IPR 229) (citations omitted).
The key consideration is whether a person reading the claims is able to give workable meaning to the claims. If so, then the claims are clear.
Similar to the issues discussed above in relation to the construction of the claims, the opponent submitted that the claims lacked clarity because the claims could be construed in different ways (that is, narrowly or broadly). On the narrow construction, the claims would comprise only a single scFv on the CAR and would be clear. On the broad construction, the claims could comprise multiple scFvs on the CAR and would lack clarity. The opponent also submitted that the broad construction would be absurd and should be rejected.[68] I agree with the opponent that an absurd construction should be rejected and in any event I have been able to give a workable meaning to the claims as set out above.
[68] Opponent submissions at [14] and [69].
Consequently, I am satisfied that the claims are clear.
Claims define the invention
Section 40(2)(b) requires the complete specification to end with a claim or claims defining the invention.
The opponent submitted that the claims do not define the invention described in the specification for the same reasons as given in relation to clarity. As I have discussed above, I consider that the claims are clear. Furthermore, I consider that all claims are clearly drafted in a way that defines the invention for which the applicant seeks protection.
I am therefore satisfied that all claims comply with section 40(2)(b).
Manner of manufacture
It is a requirement of paragraph 18(1)(a) that an invention be a manner of manufacture within the meaning of section 6 of the Statute of Monopolies. For a claim to satisfy the manner of manufacture requirement, there must be a threshold of inventiveness on the face of the specification. In NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd the High Court said:
“if it is apparent on the face of the specification, when properly construed, that the quality of inventiveness necessary for there to be a proper subject of letters patent under the Statute of Monopolies is absent, one need go no further.”[69]
[69] NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1995] HCA 15; (1995) 183 CLR 655 at [9].
This was acknowledged in Bristol Myers Squibb Co v F H Faulding & Co Ltd and further explained therein:
“The majority of the High Court in Philips explicitly say that their observations about a case where want of the threshold requirement of inventiveness is not apparent on the face of the specification are not necessary to their decision. And, in discussing the commencement point (what is “known”) of the inquiry about inventiveness, their Honours refer only to the Microcell principle. In our view, in the light of the authorities to which we have referred, Philips stands for the proposition (as a matter of construction of the 1990 Act) that if, on the basis of what was known, as revealed on the face of the specification, the invention claimed was obvious or did not involve an inventive step – that is, would be obvious to the hypothetical non inventive and unimaginative skilled worker in the field (Minnesota at 260 per Barwick CJ) – then the threshold requirement of inventiveness is not met.”[70]
[70] Bristol Myers Squibb Co v F H Faulding & Co Ltd [2000] FCA 316 at [30].
It is clear from the body of case law[71] that the threshold is taken from “the face of the specification” rather than the state of the art at the relevant time. As mentioned in the above passage, the High Court said, in Commissioner of Patents v Microcell Limited:
“We have in truth 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. A claim for nothing more than that cannot be subject matter for a patent and the position cannot be affected either by the fact that nobody thought of doing the thing before, or by the fact that, when somebody did think of doing it, it was found to be a good thing to do.”[72]
[71] D’Arcy v Myriad Genetics Inc [2015] HCA 35 at [125]-[131].
[72] Commissioner of Patents v Microcell Limited (1959) 102 CLR 232 at [15].
The opponent submitted that, on the face of the specification, “the idea of customising spacer lengths for different targets” was known and did not meet the threshold for inventiveness. Furthermore, on the face of the specification, all of the components of the CAR construct were already known in the art and the opponent submitted that there was no invention in merely putting them together.
In my view, the presently claimed invention is not as straight forward as the use of known materials in the manufacture of known articles for the purpose of which their known properties make those materials suitable. On the face of the specification, CARs were known, including CD19-specific CARs, as well as methods of providing nucleic acids encoding them and transducing them into host cells. The specification itself further reveals that the individual components, such as the scFv encoded by SEQ ID NO:3, the spacer encoded by SEQ ID NO:21, transmembrane domains, CD3ζ signalling domain and costimulatory domains, were all known in the art. Therefore, on the face of the specification itself, each of the components were known and were used for their known purposes where their known properties make them suitable. However, even where the parts were known individually, the sum of parts is an invention of a unique CAR with improved in vivo therapeutic activity. On the face of the specification alone, there is nothing to suggest that the claimed CAR construct was known.
Example 3 of the specification provides references to the sources of each of the components used therein and there was no apparent disagreement between the experts that each of the components were known in the art. The specification also shows CAR constructs which are identical except for the long and short spacers taken from the same IgG4 protein resulted in different in vivo anti-tumour activities. Consequently, even where the individual components are known in the field, it is their combinations and the manner in which they interact which gives rise to the invention, which has a different biological activity to other combinations. For this reason, I am not satisfied that the products of the present claims can be fairly categorised as nothing but a claim for the use of known materials for a known purpose.
It follows that the opponent has not established that the claimed invention fails to exceed the inventive threshold on the face of the specification.
Clear enough and complete enough disclosure
Subsection 40(2)(a) requires that the complete specification must disclose the invention in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art. In CSR Building Products Ltd v United States Gypsum Company,[73] the delegate formulated the following three steps:
1 – Construe the claims to determine the scope of the invention as claimed;
2 – Construe the description to determine what it discloses to the person skilled in the art; and
3 – Decide whether the specification provides an enabling disclosure of all the things that fall within the scope of the claims.
[73] CSR Building Products Ltd v United States Gypsum Company [2015] APO 72 at [95].
In Evolva SA,[74] the third question was reformulated as the following two-step consideration:
1 – Is it plausible that the invention can be worked across the full scope of the invention?
2 – Can the invention be performed across the full scope of the claims without undue experimentation?
[74] Evolva SA [2017] APO 57.
This approach has found approval with the Federal Court.[75] EP and UK decisions have provided some general guidance on factors that come into consideration when determining whether the specification is sufficient, including uncertainty and a lack of predictability, incomplete experimental details, and a lack of guidance in the specification including instructions on how to proceed in case of failure.[76] Most recently in ToolGen Incorporated v Fisher, Nicholas J further analysed the Explanatory Memorandum and the alignment of Australian law with that of UK and European laws of sufficiency.[77]
[75] Cytec Industries Inc v Nalco Company [2021] FCA 970; (2021) 162 IPR 202 at [143]-[146]; and ToolGen Incorporated v Fisher (No 2) [2023] FCA 794 at [167]-[175].
[76] Evolva SA [2017] APO 57 at [34].
[77] ToolGen Incorporated v Fisher (No 2) [2023] FCA 794 at [167]-[175].
The gist of the opponent’s arguments was that the only enabled embodiment relevant to the claims was the short-spacer construct described in Example 3. The opponent referred to statements given by Associate Professor Maus relating to the unpredictable nature of CAR development to point to the enormity of the undertaking required for making and identifying a CAR that provides tumour efficacy when expressed in T cells.[78] According to the opponent, the specification enables the exemplified embodiments but the description fails to provide sufficient information to enable a person skilled in the art to work with any deviation from these specific embodiments.
[78] Opponent submissions at [223]-[225].
Firstly, Professor Brown noted that Example 3 used the (G4S)3 linker while the VL and VH regions in SEQ ID NO:3 are linked by the Whitlow’s linker.[79] The opponent submitted that none of the claims were actually directed to the embodiment as described in this example because the linker between the VL and VH regions is a (G4S)3 peptide linker as opposed to the Whitlow linker appearing in SEQ ID NO:3.[80] However, other than noting that he has identified a difference, no further evidence as to the significance of the difference was provided by Professor Brown. In contrast, Associate Professor Maus provided the following:
“The two linkers that Professor Browns mentions – the (G4S)3 linker, and the Whitlow linker – are well known, standard linkers used in CAR design. The choice of one over another is, practically speaking, based on what resources you had access to at the Relevant Date. If you look at the two most efficient CARs that have already been discussed by myself and Professor Brown, the NCI CAR, on which Yescarta is based, uses the Whitlow linker and the UPENN CAR on which Kymriah is based, uses the (G4S)3 linker.”[81]
[79] Brown #1 at [134], [155], [158], [159], [160], [165], [174].
[80] Opponent submissions at [210]-[211].
[81] Maus at [119].
Based on the evidence of Associate Professor Maus, I am satisfied that a person skilled in the art would find any standard linker for the VL and VH regions of the scFv to be plausible, and it is clear that the Whitlow linker was already recognised in the art as one of the standard linkers in scFvs.
The second string of the opponent’s submissions related to the generality of the definition given for the spacer. In particular, Professor Brown noted the spacer may include additional amino acids beyond the exemplified 12-mer spacer having the specified sequence of SEQ ID NO:21, as used in Example 3.[82] Professor Brown contended that “addition of amino acids flanking the lgG4 derived hinge, particularly to the N-terminal side may result in significant conformational changes to the spacer that can have functional consequences.”[83] It is worthwhile mentioning that Professor Brown gave his first declaration when the claims were directed to a spacer comprising SEQ ID NO:51, which was only a 6-mer portion of the spacer. When giving his reply evidence after the amendments to the opposed application, Professor Brown conceded that “the likelihood is reduced by using SEQ ID NO:21.”[84]
[82] Brown #1 at [128] and [129].
[83] Brown #21 at [129].
[84] Brown #2 at [51].
Thirdly, the opponent suggested that, on the broad construction, the claimed invention could include a CAR with infinite scFvs or more generally CARs with two or more of each of the components.[85] The opponent then went on to say that such a construct would suffer from numerous issues and would be an absurd scope to claim which could not be enabled by the information provided in the specification.[86]
[85] Opponent submissions at [67](d) and Annexure D.[67](d) and
[86] Opponent submissions at [69].
On balance, as noted previously, I agree with the applicant that a person skilled in the art would not understand a CAR construct having infinite components to be embraced by the present claims.
To my mind, the question here is whether there is a general principle underlying the claimed CAR construct such that the technical contribution to the art may be seen to extend to the range of claimed CAR constructs or is limited to the specific CARs of Example 3.
Though much of the discussion was given simply in terms of the length of the spacer, contrary to the opponent’s submissions, the claims are not directed to everything falling under the umbrella of a “short spacer”. The disclosure required to offer a general principle to the claimed range is not so general as the initial discovery of the possibility of spacer length customisation for any desired target, as suggested by the opponent.[87] The spacer in the claimed construct is not just a random sequence of 15 amino acids or less but must necessarily include the short IgG4 hinge spacer of amino acid sequence of SEQ ID NO:21, which defines 12 of the 15 amino acids. I think Example 3 makes clear that there is a deliberate relationship between the chosen short IgG4 hinge spacer and the anti-CD19 scFv to ensure that the scFv presents its CDRs at a relative spatial orientation from the T cell membrane to bind the CD19 target on tumour cells. Therefore, the short IgG4 hinge spacer is not purported to be a universal spacer that can improve the in vivo efficacy of all CARs. The principle of the short IgG4 hinge spacer improving the in vivo efficacy is specific to the anti-CD19 scFv of SEQ ID NO:3.
[87] Opponent submissions at [227].
In the present case, the choice of the short IgG4 hinge spacer over the long IgG4 hinge-CH2-CH3 spacer was found to have significant impact on the efficacy of the anti-CD19 CAR-T cell therapy and spatial orientation of the scFv to the T cell membrane is maintained by the spacer comprising the amino acid sequence of SEQ ID NO:21. It is summarised by the applicant as follows:
“On the present facts, the benefit of the invention is obtained even where the other modular components of the CAR are varied. A person using such a varied CAR – for example, with a different costimulatory domain, or an additional scFv – is still using the same invention, i.e. an anti-CD19 CAR whose performance is improved by reason of it having the new spacer in association with the defined CD19 scFv.”[88]
[88] Applicant submissions at [161].
Throughout her evidence, Associate Professor Maus stressed that “it is necessary to empirically test CAR design variables as there are no general rules guiding CAR design for target molecules.”[89] These passages were referred to by the opponent to give weight to their argument that any modification would force undue burden upon a person skilled in the art. However, the statements by Associate Professor Maus were made in relation to wholesale alterations to a CAR, such as designing an entirely new CAR for a different target molecule or replacing one of the major components with an entirely different structure taken from an unrelated source.[90]
[89] Maus at [41], [63], [73] and [102].
[90] Opponent submissions at [224].
The difference between the constructs tested in Example 3 was that the long IgG4 hinge-CH2-CH3 spacer had a length of 229 amino acids while the short IgG4 hinge spacer was 12 amino acids long. Given this contrast, I think a 12-mer short IgG4 hinge spacer would be reasonably representative of other short IgG4 hinge spacer of up to 15 amino acids, which must also share the 12 amino acid sequence of SEQ ID NO:21. On the face of the specification, I think it would be plausible that the invention could be worked across the full scope of the invention including the possible extension of the spacer by up to three amino acids.
The opponent submitted that given the need for empirical testing, “the PSA would need to conduct a research program relying on trial and error to generate an alternate CAR.”[91] However,
other than pointing to the statements by Associate Professor Maus, the opponent has not provided any evidence to the effect that the claimed invention would be implausible or that testing of CARs with variations only in the spacer region by up to a total of three amino acid additions would be undue burden for a person skilled in the art. It follows that I find that the specification provides a clear enough and complete enough disclosure of the claimed invention.
[91] Opponent submissions at [225].
The opponent has not established that the specification fails to provide a clear enough and complete enough disclosure of the claimed invention.
Best method
Subsection 40(2)(aa) requires that a complete specification must ‘disclose the best method known to the applicant of performing the invention’.
In Firebelt Pty Ltd v Brambles Australia Ltd, the Full Court said:
“The requirement of s 40(2) of the Act is that the patentee is required to give the best information in his power as to how to carry out the invention. That requirement is ordinarily satisfied by including in the specification a detailed description of one or more preferred embodiments of the invention offered, with reference to drawings of specific mechanisms or structures or examples of specific process conditions or chemical formulations, depending on the field of the invention and the nature of the instruction to be conveyed. It is necessary to have regard to what is the invention claimed in the petty patent.”[92] (Emphasis in original)
[92] Firebelt Pty Ltd v Brambles Australia Ltd [2000] FCA 1689; 51 IPR 531 at [53].
The best method ground was recently considered by Besanko J in Vehicle Monitoring Systems Pty Limited v SARB Management Group Pty Ltd (No 8).[93] His Honour set out an extensive summary of principles[94] and determined that the question of whether a specification discloses the best method of performing an invention can be answered from the following considerations:
(1) the nature of the invention;
(2) the significance of what is and what is not disclosed;
(3) the public policy rationale which lies behind the best method requirement…; and
(4) the need to bear in mind that merely showing that a skilled addressee could ascertain by routine experiment the best method actually known to the applicant for the patent is not an answer to an allegation of a breach of the best method requirement.[95]
[93] Vehicle Monitoring Systems Pty Limited v SARB Management Group Pty Ltd (No 8) [2023] FCA 182.
[94] Vehicle Monitoring Systems Pty Limited v SARB Management Group Pty Ltd (No 8) [2023] FCA 182 at [400]-[410].
[95] Vehicle Monitoring Systems Pty Limited v SARB Management Group Pty Ltd (No 8) [2023] FCA 182 at [411].
The public policy rationale was also considered by Burley J in Cytec Industries Inc. v Nalco Company and was summarised as follows:
“The best method requirement provides a safeguard against a patent applicant holding back information in its possession with a view to getting the benefit of a patent monopoly without conferring on the public the full consideration for the grant of that monopoly.”[96] (citations omitted)
[96] Cytec Industries Inc. v Nalco Company [2021] FCA 970 at [152].
What is required to provide a best method of performing the invention will depend on the facts of the case. As stated by the Full Court in Les Laboratoires Servier v Apotex Pty Ltd:
“It can be accepted that there are cases where the claim is to a product or class of products and the best method requirement is satisfied by a description of the best embodiment known to the patentee at the relevant time. It can also be accepted that there are cases where the claim is to a product and there is no requirement to provide a method of using that product. It is also the case that there is no requirement actually to have carried out the best method and that a prediction will suffice (New England Biolabs, Inc v Hoffmann-La Roche AG [2004] FCA 1651; (2004) 63 IPR 524 at [33]). However, it is necessary to understand the invention itself [Expo-Net Danmark A/S v Buono-Net Australia Pty Ltd (No 2) [2011] FCA 710]. As was succinctly stated by Lord Hoffman in Kirin-Amgen Inc. v Hoechst Marion Roussel Limited [2005] RPC 9 at [104]:
‘in order to decide whether the invention has been fully enabled, you first have to decide what the invention is’.
Lord Hoffman was there addressing the sufficiency requirement, but the observation applies equally to the best method requirement. The nature of the invention will determine what is “best” in the circumstances.”[97]
[97] Les Laboratoires Servier v Apotex Pty Ltd [2016] FCAFC 27; 247 FCR 61 at [129].
Most recently, Rofe J in Boehringer Ingelheim Animal Health USA Inc v Zoetis Services LLC added:
“The disclosure of the method must be such as to relieve the skilled addressee seeking to implement the invention, including achieving the advantages associated with the invention, as at the expiry of the patent from being faced with undertaking a potentially extensive course of trial and error experiments to overcome the blind alleys and pitfalls which the patentee had already navigated or overcome as at the filing date.”[98]
[98] Boehringer Ingelheim Animal Health USA Inc v Zoetis Services LLC [2023] FCA 1119 at [636].
In Dometic Australia Pty Ltd v Houghton Leisure Products Pty Ltd, White J explained that the relevant date for the purposes of section 40(2)(aa) is the filing date of the respective divisional application.[99] In reaching this conclusion, White J specifically rejected the argument that the filing date relevant for best method should be taken from the filing date of the parent application.[100] Therefore, I understand that I must determine whether the applicant has disclosed the best method of performing the invention known to them on the filing date of the opposed application of 13 June 2018.
What is the invention for which the best method must be described?
[99] Dometic Australia Pty Ltd v Houghton Leisure Products Pty Ltd [2018] FCA 1573 at [229]-[234].
[100] Dometic Australia Pty Ltd v Houghton Leisure Products Pty Ltd [2018] FCA 1573 at [233].
The applicant characterised their invention as “a spacer that, when used with a particular CD19 scFv as part of a CAR, achieves increased in vivo efficacy when transduced into a CAR-T cell.”[101] The opponent characterised the invention by identifying the feature common to the various claims, namely “a CD19 specific CAR design incorporating a short (hinge only) spacer”.[102] However, the opponent added that the nature of the invention incorporates everything from the design of the CAR construct to the engineering steps to have T cells expressing the CAR and the effective deployment of the CAR-T cell therapy using the construct are all fundamental aspects, irrespective of the scope of the claimed invention.[103]
[101] Applicant submissions at [182].
[102] Opponent submissions at [282].
[103] Opponent submissions at [283] and [285].
At the hearing, the applicant put forward that the invention is the CAR rather than any special way of administering CAR-T cell therapy or a special way of expressing the CAR construct in T cells. With reference to Les Laboratoires Servier v Apotex Pty Ltd, above, the applicant noted that the aspects of manufacture are important for products where the invention lies in the process by which they are made. In contrast, the applicant submitted, the present invention is the CAR itself.
Does the invention lie in the CAR construct or in engineering techniques for preparing CAR-T cells for use in therapy?
It is clear that the invention lies in the anti-CD19 CAR constructs with the short IgG4 hinge spacer and the fact that they can be expressed on T cells. Consequently, the invention must lie in both the constructs and CAR-T cells expressing them. I do not consider that the invention for which a best method must be disclosed extends to new expression systems, new engineering techniques for CAR-T cells or to the use of the constructs in clinical CAR-T cell therapy.
What does the specification disclose?
Under the heading “Experimental”, the specification provides three examples of customising the spacer length for recognition of target molecules with CAR-T cells. Example 3 describes the customisation of the spacer length for optimal in vivo efficacy and recognition of CD19 with CAR-T cells. The example steps through the collection of blood samples from healthy donors, immunophenotyping the blood samples, provision of tumour cell lines, vector construction and preparation of a modified lentivirus encoding the anti-CD19 CAR, generation of the T cell line expressing the anti-CD19 CAR, in vitro assays, and experiments in mice.
There was no suggestion by the opponent that the disclosure provided in Example 3 is insufficient to prepare anti-CD19 CAR constructs with the short IgG4 hinge spacer and produce T cells expressing them.
I conclude that a person skilled in the art would have appreciated how to prepare CD19 CAR constructs with the short IgG4 hinge spacer and produce T cells expressing them from a reading of the specification as a whole and in the light of the common general knowledge.
Did the applicant know anything better?
The opponent’s concern lay with the further development of anti-CD19 CARs and CAR-T cell therapies conducted by the applicant and its licensees during the period from after the filing of the parent application and up to 13 June 2018, when the opposed application was filed.[104] The opponent provided a history of Juno Therapeutics, a company formed in 2013 and led by the inventors of the opposed application to develop cell-based pharmaceuticals involving CAR-T cells.[105] The opponent had also tasked Associate Professor DeSelm and Dr Burns with reviewing contemporaneous documents relating to research and development activities.[106]
[104] Opponent submissions at [288].
[105] Opponent submissions at [289]-[292].
[106] Opponent submissions at [293].
These research and development activities by Juno Therapeutics culminated in the approval of the product BREYANZI by the US Food and Drug Administration in February 2021.[107] According to Dr Burns, the structure of BREYANZI was published in a 2015 research paper and “is identical to that disclosed in the [parent] application”,[108] which is also identical to that disclosed in the opposed application. However, I note that the approval occurred after the filing date of the opposed application. Moreover, Juno Therapeutics had been acquired by Celgene, and subsequently by Bristol Myers Squibb, prior to the approval of the BREYANZI product.[109]
[107] Opponent submissions at [290].
[108] Burns at [14]-[15].
[109] Opponent submissions at [289].
Associate Professor DeSelm was provided with the opposed application, annual reports filed by Juno Therapeutics for the years 2014 through to 2017 and 11 documents authored by any one or more of the named inventors for the opposed application.[110] Following a review of these documents, Associate Professor DeSelm opined that the opposed application fails to disclose information known to the applicant as being better than the information included in the specification at the time of filing the opposed application. The opponent summarised the relevant points as follows:
a.It was possible to use CAR-T cell ablation via cetuximab antibody targeting of the EGFRt coexpression marker of the engineered CAR-T cells as an ablation safety switch in the case of CAR-T cell related toxicity;
b.Coexpression of the CAR and EGFRt cell marker needed the construct to encode a 2A self-cleaving peptide and the P2A peptide is better than T2A.
c.HER2t is a more stable and effective tag in CAR therapy and thus could be used instead of or as an alternative to EGFRt.
d.Swapping a functional fully humanised FMC63 scFv for the murine FMC63 scFv of the FMC63-containing CAR used in clinical trials reduced immune rejection, and therefore results in a CAR-T cell with superior in vitro and in vivo function;
e.High functioning CARs with an optimised fusion site extension of the CD28 sequence by two additional amino acids reduced immunogenicity concerns without negatively affecting cytotoxicity, cytokine release and proliferation in vivo; and
f.The Applicants' preferred lentivirus transduction method involving specific transfection conditions, transfection culture components, and a particular clinical grade lentiviral transfection vector.[111]
[110] DeSelm at [14].
[111] Opponent submissions at [297].
Associate Professor DeSelm was particularly concerned with the efficacy and safety of the CAR-T cell therapy using various anti-CD19 CARs in the clinical setting.[112] In the eyes of Associate Professor DeSelm, insofar as in-human clinical trials had been conducted by the time the opposed application was filed, the preclinical data given in the specification is wholly inadequate for a person skilled in the art to draw any conclusions on clinical safety. However, Associate Professor DeSelm also noted that “the preclinical data in immunodeficient mice provides evidence for the desired biological effect of the CAR T-cells and may predict efficacy in patients.”[113]
[112] DeSelm at [41]-[45].
[113] DeSelm at [43].
The applicant submitted that the opponent has not provided any evidence showing that the applicant considered that any of the identified elements, or even the marketed product, was superior to the product disclosed in Example 3.[114] Moreover, much of the purported undisclosed information relates to patient care, CAR-T immunotherapy protocols, post-transduction processes for culturing and expanding the modified T cells, the transfection viral vector or to alternatives for additional components co-expressed during CAR transduction.[115]
[114] Applicant submissions at [190].
[115] Applicant submissions at [186]-[203]
As noted above, the opponent’s evidence points to the BREYANZI product and the CAR construct of the opposed application being identical. Consequently, I cannot see how BREYANZI itself represents a better method than an identical disclosure made in the specification. The research and development carried out by Juno Therapeutics between the filing of the parent application and the filing of the opposed application was not limited to the anti-CD19 CAR construct that eventually became BREYANZI. Juno Therapeutics also carried out research and development in relation to other CAR constructs, general improvements in the engineering of CAR-T cells and the use of CAR-T cells in therapy.
I also note that Juno Therapeutics carried out their research and development, having obtained exclusive license from the applicant to do so. While the evidence of the opponent establishes that inventors listed for the opposed application were involved in the research and development after the filing of the parent application, the actual knowledge that can be attributed to the applicant is not apparent from the evidence.
I agree with the applicant that there is no evidence that the applicant was aware of a better anti-CD19-specific CAR construct having a short IgG4 hinge spacer than that disclosed in Example 3. Moreover, the relevant invention for which the best method must be described does not relate to the clinical application or to a new engineering technique for CAR-T cells. Consequently, the knowledge accumulated in relation to these other matters was not required to be included in the specification.
Conclusion on the best method requirement
The applicant has provided a detailed worked example of preparing anti-CD19 CAR constructs having a short IgG4 hinge spacer and carrying out additional testing to verify its efficacy in binding to and killing target cancer cells. While the opponent has shown that the inventors have continued to conduct research and development in the field of CAR T-cell therapy up to the filing date of the opposed application, there is no evidence that that applicant knew of, or considered, the later information to be better with respect to anti-CD19 CAR-T cells expressing the CAR constructs of the present invention.
The opponent has not established that the opposed application does not include the best method known to the applicant at time of filing the opposed application.
Support
Subsection 40(3) as amended by the Raising the Bar Act requires that the claims must be supported by matter disclosed in the specification. Burley J in Merck Sharp & Dohme Corporation v Wyeth LLC (No 3):
“In CSR Building Products Ltd v United States Gypsum Company [2015] APO 72, Dr S D Barker adopted the summary provided by Aldous J in Schering Biotech at 252 – 253, which has been often followed in the United Kingdom (emphasis added):
…to decide whether the claims are supported by the description it is necessary to ascertain what is the invention which is specified in the claims and then compare that with the invention which has been described in the specification. Thereafter the court’s task is to decide whether the invention in the claims is supported by the description. I do not believe that the mere mention in the specification of features appearing in the claim will necessarily be a sufficient support. The word “support” means more than that and requires the description to be the base which can fairly entitle the patentee to a monopoly of the width claimed.
That approach encapsulates broadly the claim support obligation under s 40(3). To it may be added the requirement that the technical contribution to the art must be ascertained. Where it is a product, it is that which must be supported in the sense that the technical contribution to the art disclosed by the specification must justify the breath of the monopoly claimed.”[116]
[116] Merck Sharp & Dohme Corporation v Wyeth LLC(No 3) [2020] FCA 1477 at [546]-[547].
In Cytec Industries Inc. v Nalco Company, Burley J made a similar observation.[117] Similarly, Nicholas J most recently considered the ground of support and affirmed the approach taken by Burley J.[118] Nicholas J also stressed the following:
“The question whether a disclosure in a patent application fairly entitles the patentee to a monopoly of the width claimed calls for an assessment of the patentee’s contribution to the art, which must be weighed against the scope of the patentee’s monopoly as defined by the claims. The monopoly, according to UK and European authorities, must be justified by the technical contribution to the art that arises from the disclosure of the specification.”[119]
[117] Cytec Industries Inc. v Nalco Company [2021] FCA 970 at [120].
[118] ToolGen Incorporated v Fisher (No 2) [2023] FCA 794 at [391]-[395].
[119] ToolGen Incorporated v Fisher (No 2) [2023] FCA 794 at [396].
A useful approach to determining whether the requirements of support are satisfied was set out in CSR Building Products Limited v United States Gypsum Company:
i.construe the claims to determine the scope of the invention as claimed,
ii.construe the description to determine the technical contribution to the art, and
iii.decide whether the claims are supported by the technical contribution to the art.[120]
[120] CSR Building Products Limited v United States Gypsum Company [2015] APO 72 at [115].
At the hearing, the opponent put forward that the claims fail to meet the requirements of support due to the fact that they are not confined to the short-spacer CAR construct provided in Example 3. The opponent referred to Professor Brown’s remark in his declaration with regard to the breadth of the claims in comparison to the technical contribution to the art made in the opposed application:
“Overall, in my view, the Opposed Application does not appear to advance the field in any significant way and in fact appears to broadly claim CAR constructs that were being considered and evaluated in the field as at August 2012. Indeed, the claimed invention appears particularly broad, in my view, given the relatively limited testing and data presented in the Opposed Application. Interestingly, the claimed invention is limited to CD19-specific CAR-T cells which I thought was unusual, given that the vast majority of the experimental data and most convincing results relate to ROR1-specific CAR-T cells (see, Example 1, starting on page 57).”[121] (emphasis added to show portion quoted by the opponent)
[121] Brown #1 at [99].
The nature of the invention in the opposed application resides in the CAR construct having a scFv defined at least by the six CDRs present in the amino acid sequence encoded by SEQ ID NO:3 and a spacer having a length of 15 amino acids or less and comprising the amino acid sequence encoded by SEQ ID NO:21 between the scFv and the transmembrane domains. The claimed spacer essentially acts as a tether to ensure that the scFv defined at least by the six CDRs present in the amino acid sequence encoded by SEQ ID NO:3 is maintained at a spatial orientation relative to the host cell such that the target CD19 can be bound effectively. The applicant’s contribution to the art resides in providing the claimed CAR construct with the specific pairing of the spacer comprising SEQ ID NO:21 having a length of 15 amino acids or less between the anti-CD19 scFv of SEQ ID NO:3 and the transmembrane domain.
The opponent further submitted that “The Applicants cannot rely on providing a principle of general application (e.g., customizing a spacer length for a particular target) because each CAR is unpredictable (see [319]-[321] of Toolgen).”[122] In this regard, the opponent relied on statements by Associate Professor Maus to the effect that designing CAR constructs is unpredictable and there are no general design rules that hold true across all CARs.[123]
[122] Opponent submissions at [227].
[123] Maus at [38], [39], [41], [63], [65], [73] and [102].
The applicant submitted that the lack of general design rules and reliability across CARs pointed to by Associate Professor Maus relate to major modifications, such as replacing a component with a completely different structure or a ‘clean slate’ design task.[124] For example, making a wholesale change on the scFv from one which binds CD19 to another that binds CD20, one cannot expect the changed CAR to work effectively without modifying the remainder of the construct. However, Associate Professor Maus makes it clear that selecting the short IgG4 hinge spacer for the scFv of SEQ ID NO:3 is the applicant’s contribution to the art.
[124] Applicant submissions at [147].
The claimed invention does not extend to cover any and all CAR constructs with any “short” spacer. The applicant identified that spacer customisation was beneficial and put it into practice with the exemplified constructs. With regard to the CD19-specific CARs, the applicant’s contribution to the art lies in identifying that for a scFv encoded by the amino acid sequence of SEQ ID NO:3, a short IgG4 hinge spacer comprising the amino acid sequence encoded by SEQ ID NO:21 was beneficial over a long IgG4 hinge-CH2-CH3 spacer. The technical contribution lies in this spacer selection which ensures that the CD19-specific scFv of SEQ ID NO:3 is held in a specific spatial orientation relative to the transmembrane domain to promote better binding of the target CD19 on tumour cells.
I do not think that the claims are broader than the applicant’s contribution to the art. The claimed CAR constructs maintain a minimum requirement across the board for the scFv component to have at least the six CDRs present in the amino acid sequence encoded by SEQ ID NO:3, and the spacer component to comprise the amino acid sequence encoded by SEQ ID NO:21, be no longer than 15 amino acids in length, and to be located between the scFv and the transmembrane domains.
The opponent has not established that the claims lack support.
Utility
Subsection 18(1)(c) of the Act requires that the invention, so far as claimed in any claim, is useful. The ground of utility was considered by the Full Court of the Federal Court in H Lundbeck A/S v Alphapharm Pty Ltd., Emmett J stated:
“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.”[125]
[125] H Lundbeck A/S v Alphapharm Pty Ltd. [2009] FCAFC 70; 81 IPR 228 at [247].
In Apotex Pty Ltd v AstraZeneca AB (No 4), Jagot J pointed out that lack of utility requires evidence, not just speculation:
“Ultimately, an asserted lack of utility must be established by appropriate evidence, not be mere speculation that the invention will not work or meet the promise set out in the specification.”[126]
[126] Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162 at [352].
Even accepting that it was routine to modify the spacer component of any given CAR, the short IgG4 hinge spacer is merely one of numerous possible choices. In the absence of any direction as to which of the many choices is likely to successful, even at the low threshold of simply reaching clinical usefulness, the person skilled in the art may well have reached for a different spacer. Particularly in light of the successful prior art CARs having CD28 and CD8α spacers and the unsuccessful Baylor construct having an IgG1 spacer, the common general knowledge would not have directed the person skilled in the art towards IgG-based spacers.
The pairing of a scFv of SEQ ID NO:3 with a short spacer comprising the amino acid sequence of SEQ ID NO:21 in a CAR construct could at best be characterised as “obvious to try” when seeking to provide a clinically useful alternative to the NCI and UPENN constructs in the sense described by Rich J and set out above. It is a possible outcome that could be reached by a person skilled in the art who was exploring the idea of experimenting with the spacer domain and trying each of numerous possible choices until they possibly arrived at a successful result, but this does not necessarily make the claimed invention obvious.
It follows that the claims do not lack inventive step in light of the common general knowledge alone.
Inventive step in light of prior art documents
In their submissions, the opponent relied on the following prior art documents:
D2:WO 2011/056894 A2 (JENSEN, MICHAEL C.) 12 May 2011
D3:KOWOLIK et al.: “CD28 Costimulation Provided through a CD19-Specific Chimeric Antigen Receptor Enhances In vivo Persistence and Antitumor Efficacy of Adoptively Transferred T Cells”, CANCER RESEARCH, 2006, vol. 66, no. 22, pp. 10995-11004.
D6:GUEST et al.: “The Role of Extracellular Spacer Regions in the Optimal Design of Chimeric Immune Receptors. Evaluation of Four Different scFvs and Antigens”, JOURNAL OF IMMUNOTHERAPY, 2005, vol. 28, no. 3, pp. 203-211
D45:HOMBACH et al.: “T Cell Activation by Antibody-Like Immunoreceptors: The Position of the Binding Epitope within the Target Molecule Determines the Efficiency of Activation of Redirected T Cells”, THE JOURNAL OF IMMUNOLOGY, 2007, vol. 178, pp. 4650-4657
D7:HOMBACH et al.: “Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc ‘spacer’ domain in the extracellular moiety of chimeric antigen receptors avoids ‘off-target’ activation and unintended initiation of an innate immune response”, GENE THERAPY, 2010, vo. 17, pp. 1206-1213
I understand the opponent’s case in relation to the prior art documents to be that the claims lack inventive step in light of the common general knowledge together with each of D2, D3, D6, D45 or D7 individually. There was no general disagreement on the relevant information provided by each of the prior art documents.
D2 is a patent document directed to the development of markers for co-expression with CARs for transduced T cell selection.[187] The marker is a truncated EGFR sequence and co-expressed with a CAR otherwise comprising the VH and VL segments of the CD19-specific antibody FMC63, an IgG1 hinge-CH2-CH3 spacer, CD28 transmembrane and cytoplasmic signalling domains and CD3ζ cytoplasmic domain.[188]
[187] D2 at abstract.
[188] D2 at [63].
D3 is a journal article describing a second-generation CAR comprising a scFv derived from FMC63, a modified IgG4 hinge-CH2-CH3 spacer, CD28 transmembrane and cytoplasmic signalling domains and CD3ζ cytoplasmic domain.[189]
[189] D3 page 10996 left column paragraph 1, Figure 2.
In the opponent’s submissions, there is only one feature from each of D2 and D3 which is different to the claimed CARs, namely the incorporation of a shorter spacer of 15 amino acids or less, which would have been obvious and mere routine to achieve.[190] Neither D2 nor D3 discuss the IgG4 hinge-only spacer, discussing the long hinge-CH2-CH3 spacers of IgG1 and IgG4 origins, respectively. As such, and for the reasons given above in relation to inventive step in light of the common general knowledge alone, I am not satisfied that the claims lack inventive step in light of either D2 or D3 and the common general knowledge.
[190] Opponent submissions at [174]-[175].
D6 is a journal article describing the investigation into the role of the spacer domain in CAR constructs by introducing a full IgG1 hinge-CH2-CH3 domain as a spacer or no spacer at all.[191] One of the tested constructs targeted CD19 but the construct without a spacer region out-performed the construct with a spacer.[192]
[191] D6 abstract, page 205 left column paragraph 2.
[192] D6 page 208 left column paragraph 2; Maus at [55].
D45 is a journal article showing that CAR-T cell activation was more efficient when targeting a membrane proximal epitope than the membrane-distal epitope when using the full IgG1 hinge-CH2-CH3 domain as a spacer for a construct targeting the carcinoembryonic antigen.[193]
[193] D45 abstract, Figure 8, page 4655 left column paragraph 2.
In the opponent’s submissions, D6 and D45 provide strong motivation to optimise the spacer length if a person skilled in the art was seeking for a useful alternative to the common general knowledge of NCI and UPENN CD19 CAR constructs. However, D6 actively teaches away from having any spacer in a CAR construct targeting CD19 and D45 teaches a person skilled in the art to target a membrane-proximal epitope using a long spacer. As above, it has not been established that spacer length optimisation forms part of the common general knowledge. As such, and for the reasons given above in relation to inventive step in light of the common general knowledge alone, I am not satisfied that the claims lack inventive step in light of either D6 or D45 and the common general knowledge.
D7 is a journal article describing the modification of IgG1 hinge-CH2-CH3 component as a spacer to avoid off-target activation and unintended initiation of an innate immune response against the CAR constructs.[194] The opponent submits that the person skilled in the art would take on board the modification described in D7 to avoid off-target activation and further remove the CH2 and CH3 domains from the modified spacer following a routine spacer length optimisation process. As above, it has not been established that spacer length optimisation forms part of the common general knowledge and no explanation has been provided for further swapping the IgG1 spacer for an IgG4 spacer. As such, and for the reasons given above in relation to inventive step in light of the common general knowledge alone, I am not satisfied that the claims lack inventive step in light of D7 and common general knowledge.
[194] D7 abstract, page 1207 left column paragraph 1, page 1208 left column paragraph 2.
Accordingly, obviousness in light of any one of D2, D3, D6, D45 or D7 is not made out. The reasoning leads to a conclusion that further combinations of these documents or additional documents would also not deprive the claims of inventive step.
Conclusion on inventive step
The opponent has not established that the claims lack inventive step in light of the common general knowledge, alone or in combination with any of the identified prior art documents.
Conclusion
The opposition to grant is unsuccessful on all grounds. Consequently, subject to appeal, I direct that the application proceeds to grant.
Costs
Neither party made submissions as to costs. The normal approach is that costs should follow the event. I see no sufficient reason to depart from this approach. The opposition is unsuccessful. Accordingly, I award costs in accordance with Schedule 8 against the opponent, Rozenberg & Co Pty Ltd.
M. Umehara
Delegate of the Commissioner of Patents
Annex: Claims
1. A nucleic acid encoding a chimeric receptor, the chimeric receptor comprising an extracellular domain consisting of a single chain variable fragment (scFv) and an extracellular polypeptide spacer, a transmembrane domain and an intracellular signaling domain, wherein:
(a) the scFv binds to a CD19 and comprises a variable light chain (VL) domain comprising a CDRL1, a CDRL2, and a CDRL3 of the amino acid sequence encoded by SEQ ID NO:3, and a variable heavy chain (VH) domain comprising a CDRH1, a CDRH2, and a CDRH3 of the amino acid sequence encoded by SEQ ID NO:3;
(b) the polypeptide spacer is located between the scFv and the transmembrane domain, wherein the polypeptide spacer is 15 amino acids or less in length and comprises the amino acid sequence of SEQ ID NO:21; and
(c) the intracellular signaling domain comprises a CD3ζ signaling domain and a costimulatory domain.
2. A nucleic acid encoding a chimeric receptor, the nucleic acid comprising:
(a) a polynucleotide encoding a single chain variable fragment (scFv) that binds to CD19, wherein the scFv comprises:
a variable light chain (VL) domain comprising a VL domain present in the amino acid sequence encoded by SEQ ID NO:3, and a variable heavy chain (VH) domain comprising a VH domain present in the amino acid sequence encoded by SEQ ID NO:3; or
the amino acid sequence encoded by SEQ ID NO:3;(b) a polynucleotide encoding a transmembrane domain;
(c) a polynucleotide encoding a polypeptide spacer located between the scFv and the transmembrane domain, wherein the polypeptide spacer is 15 amino acids or less in length and comprises the amino acid sequence of SEQ ID NO:21; and
(d) a polynucleotide encoding an intracellular signaling domain that comprises a CD3ζ signaling domain and a costimulatory domain.
3. The nucleic acid of claim 1, wherein the ligand-binding domain comprises a variable heavy chain (VH) domain having at least 90% identity to the VH domain present in the amino acid sequence encoded by SEQ ID NO:3; and a variable light chain (VL) domain having a least 90% sequence identity to the VL domain present in the amino acid sequence encoded by SEQ ID NO:3.
4. The nucleic acid of claim 1 or 3, wherein the scFv comprises a CDRL1 sequence of RASQDISKYLN, a CDRL2 sequence of SRLHSGV, and a CDRL3 sequence of GNTLPYTFG and a CDRH1 sequence of DYGVS, a CDRH2 sequence of VIWGSETTYYNSALKS, and a CDRH3 sequence of YAMDYWG.
5. The nucleic acid of any one of claims 1, 3 or 4, wherein the scFv comprises a variable heavy chain domain present in the amino acid sequence encoded by SEQ ID NO:3 and a variable light chain domain present in the amino acid sequence encoded by SEQ ID NO:3.
6. The nucleic acid of any of claims 1-5, wherein the scFv comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain separated by a peptide linker.
7. The nucleic acid of claim 6, wherein the scFv has a VL-linker-VH orientation.
8. The nucleic acid of any one of claims 1-7, wherein the polypeptide spacer is 12 amino acids in length.
9. The nucleic acid of any one of claims 1-7, wherein the polypeptide spacer consists of the amino acid sequence of SEQ ID NO:21.
10. The nucleic acid of any one of claims 1-9, wherein the transmembrane domain comprises a transmembrane domain of a CD8 or of a CD28.
11. The nucleic acid of any one of claims 1-10, wherein the transmembrane domain comprises a transmembrane domain of a CD28 comprising the amino acid sequence encoded by SEQ ID NO:5, or the amino acid sequence MFWVLVVVGGVLACYSLLVTVAFIIFWV.
12. The nucleic acid of any one of claims 1-11, wherein the costimulatory domain comprises:
the signaling domain of a 4-1BB or a modified version thereof; or
the signaling domain of a CD28 or a modified version thereof.13. The nucleic acid of claim 12, wherein the 4-1BB signaling domain comprises amino acids 214-255 of SEQ ID NO:15 or comprises the amino acid sequence encoded by SEQ ID NO:6.
14. The nucleic acid of any one of claims 1-13, wherein the CD28 signaling domain comprises amino acids 180-220 of SEQ ID NO:14 or comprises a modified version thereof comprising an LL → GG substitution located at positions 186-187 of SEQ ID NO:14.
15. The nucleic acid of any one of claims 1-14, wherein the CD3ζ signaling domain comprises the amino acid sequence encoded by SEQ ID NO:7.
16. The nucleic acid of any one of claims 1-15, wherein:
the scFv has a VL-linker-VH orientation;
the polypeptide spacer comprises the amino acid sequence of SEQ ID NO:21;
the transmembrane domain comprises the amino acid sequence encoded by the polynucleotide sequence set forth in SEQ ID NO:5; and
the intracellular signaling domain comprises the amino acid sequence encoded by the polynucleotide sequence set forth in SEQ ID NO:6 and the amino acid sequence encoded by SEQ ID NO:7.17. The nucleic acid of any one of claims 1 and 3-16, wherein:
the scFv comprises a VH domain present in the amino acid sequence encoded by SEQ ID NO:3 and a VL domain present in the amino acid sequence encoded by the sequence of SEQ ID NO:3;
the polypeptide spacer comprises the amino acid sequence of SEQ ID NO:21;
the transmembrane domain comprises the amino acid sequence encoded by SEQ ID NO:5; and
the intracellular signaling domain comprises the amino acid sequence encoded by SEQ ID NO:6 and the amino acid sequence encoded by SEQ ID NO:7.18. The nucleic acid of any one of claims 1-17, wherein the scFv is encoded by the sequence set forth in SEQ ID NO:3.
19. The nucleic acid of any one of claims 1-18, wherein the nucleic acid comprises:
(a) the sequence set forth in SEQ ID NO:3 encoding the scFv;
(b) the sequence set forth in SEQ ID NO:4 encoding the polypeptide spacer;
(c) the sequence set forth in SEQ ID NO:5 encoding the transmembrane domain;
(d) the sequence set forth in SEQ ID NO:6 encoding the costimulatory domain; and
(e) the sequence set forth in SEQ ID NO:7 encoding the CD3ζ signaling domain.20. The nucleic acid of any one of claims 1-19, wherein the nucleic acid encodes a chimeric receptor encoded by a nucleic acid construct comprising the sequence set forth in SEQ ID NO:10.
21. A chimeric receptor polypeptide encoded for by the nucleic acid of any one of claims 1-20.
22. A chimeric receptor polypeptide, the chimeric receptor comprising an extracellular domain consisting of a single chain variable fragment (scFv) and an extracellular polypeptide spacer, a transmembrane domain and an intracellular signaling domain, wherein:
(a) the scFv binds to a CD19 and comprises a variable light chain (VL) domain comprising a CDRL1, a CDRL2, and a CDRL3 of the amino acid sequence encoded by SEQ ID NO:3, and a variable heavy chain (VH) domain comprising a CDRH1, a CDRH2, and a CDRH3 of the amino acid sequence encoded by SEQ ID NO:3;
(b) the polypeptide spacer is located between the scFv and the transmembrane domain, wherein the polypeptide spacer is 15 amino acids or less in length and comprises the amino acid sequence of SEQ ID NO:21; and
(c) the intracellular signaling domain comprises a CD3ζ signaling domain and a co]stimulatory domain.
23. A chimeric receptor polypeptide, the chimeric receptor comprising:
(a) a ligand binding domain that binds to a CD19, wherein the ligand binding domain comprises a single chain variable fragment (scFv) that comprises:
a variable light chain (VL) domain comprising a VL domain present in the amino acid sequence encoded by SEQ ID NO:3, and a variable heavy chain (VH) domain comprising a VH domain present in the amino acid sequence encoded by SEQ ID NO:3; or
the amino acid sequence encoded by SEQ ID NO:3;(b) a transmembrane domain;
(c) a polypeptide spacer located between the ligand binding domain and the transmembrane domain, wherein the polypeptide spacer is 15 amino acids or less in length and comprises the amino acid sequence of SEQ ID NO:21; and
(d) an intracellular signaling domain that comprises a CD3ζ signaling domain and a costimulatory domain.
24. The chimeric receptor polypeptide of claim 22 or 23, wherein:
(a) the scFv is encoded by the sequence set forth in SEQ ID NO:3;
(b) the polypeptide spacer is encoded by the sequence set forth in SEQ ID NO:4;
(c) the transmembrane domain is encoded by the sequence set forth in SEQ ID NO:5;
(d) the costimulatory domain is encoded by the sequence set forth in SEQ ID NO:6; and
(e) the CD3ζ signaling domain is encoded by the sequence set forth in SEQ ID NO:7.
25. A chimeric receptor polypeptide encoded by a nucleic acid construct comprising the sequence set forth in SEQ ID NO:10.
26. An expression vector comprising the nucleic acid of any one of claims 1-20 or a nucleic acid encoding the chimeric receptor polypeptide of any one of claims 21-25.
27. The expression vector of claim 26, further comprising a polynucleotide encoding a marker sequence, wherein the polynucleotide encoding the marker sequence is operably linked in frame with the nucleic acid encoding the chimeric receptor.
28. The expression vector of claim 27, wherein the nucleic acid encoding the chimeric receptor and the polynucleotide encoding the marker sequence are separated by a polynucleotide encoding a cleavable linker.
29. The expression vector of claim 27 or 28, wherein the marker sequence is a truncated EGFR sequence.
30. The expression vector of claim 29, wherein the truncated EGFR sequence is encoded by the polynucleotide of SEQ ID NO:9.
31. The expression vector of any one of claims 28-30, wherein the cleavable linker comprises a T2A peptide.
32. The expression vector of claim 31, wherein the T2A peptide is encoded by the polynucleotide of SEQ ID NO:8.
33. An expression vector encoding the amino acid sequence
MLLLVTSLLLCELPHPAFLLIPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGSTSGSGKPGSGEGSTKGEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSESKYGPPCPPCPMFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRLEGGGEGRGSLLTCGDVEENPGPRMLLLVTSLLLCELPHPAFLLIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFM.
34. A host cell comprising the nucleic acid of any one of claims 1-20, the chimeric receptor polypeptide of any one of claims 21-25, or the expression vector of any one of claims 26-33.
35. The host cell of claim 34, wherein the host cell is an immune cell.
36. The host cell of claim 34 or 35, wherein the host cell is a lymphocyte that is CD45RA-, CD45RO+ and CD62L+.
37. The host cell of claim 35 or 36, wherein the host cell is a T cell.
38. The host cell of any one of claims 34-37, wherein the host cell is a CD8+ T cell or a CD4+ T cell.
39. The host cell of any one of claims 34-38, wherein the host cell is a CD8+ T cell selected from the group consisting of naïve CD8+ T cells, central memory CD8+ T cells, effector memory CD8+ T cells and bulk CD8+ T cells.
40. The host cell of claim 39, wherein the CD8+ T cell is a central memory T cell, wherein the central memory T cell is CD45RO+, CD62L+ and CD8+.
41. The host cell of any one of claims 34-38, wherein the host cell is a CD4+ T cell selected from the group consisting of naïve CD4+ T cells, central memory CD4+ T cells, effector memory CD4+ T cells, and bulk CD4+ T cells.
42. The host cell of claim 41, wherein the CD4+ T cell is a naïve CD4+ T cell, wherein the naïve CD4+ T cell is CD45RA+, CD62L+ and CD4+, and CD45RO-.
43. A composition comprising the host cell of any one of claims 34-42 in a pharmaceutically acceptable excipient.
44. The composition of claim 43, wherein the composition comprises a CD4+ T cell host cell and/or a CD8+ T cell host cell.
45. The composition of claim 43 or 44, wherein the composition comprises a plurality of CD4+ T cells expressing the chimeric receptor and a plurality of CD8+ T cells expressing the chimeric receptor, in about a 1:1 ratio in the composition.
46. An in vitro method for preparing a host cell, comprising:
(a) introducing the nucleic acid of any one of claims 1-20 or the expression vector of any one of claims 26-33 into a T cell; and
(b) culturing the cells in the presence of anti-CD3 and/or anti CD28, and at least one homeostatic cytokine.
47. The method of claim 46, wherein the lymphocyte population comprises a lymphocyte that is CD45RA-, CD45RO+ and CD62L+.
48. The method of claim 46 or 47, wherein the lymphocyte population comprises a T cell, wherein the T cell is a CD8+ T cell or a CD4+ T cell.
49. The method of claim 48, wherein:
the CD8+ T cell is selected from the group consisting of naïve CD8+ T cells, central memory CD8+ T cells, effector memory CD8+ T cells and bulk CD8+ T cells;
the CD8+ T cell is a central memory T cell, wherein the central memory T cell is CD45RO+, CD62L+ and CD8;
the CD4+ T cell is selected from the group consisting of naïve CD4+ T cells, central memory CD4+ T cells, effector memory CD4+ T cells, and bulk CD4+ T cells; and/or
the CD4+ T cell is a naïve CD4+ T cell, wherein the naïve CD4+ T cell is CD45RA+, CD62L+ and CD4+, and CD45RO-.
0
28
0