Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application claims priority to foreign applications SG1020201295P, filed on 22 December 2020, and SG10202107937Q, filed on 21 July 2021, and PCT application PCT/SG2021/050818, filed on 22 December 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective filing date is 22 December 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 31 October 2023 is being considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-27 are the original claims filed on 22 June 2023. In the preliminary amendment of 31 October 2023, claims 2-5, 7, 8, 10, 11, 14, 16-18, and 23-26 are amended and claims 3, 6, 9, 12, 15, 22, and 27 are canceled. Claims 1, 2, 4, 5, 7, 8, 10, 11, 13, 14, 16-21, and 23-26 are pending and the subject of this office action.
Drawings
Figures 3 and 7 are objected to due to critical features being illegible (the identifying text in the schematics). As a result, the drawings are not in agreement with rule 11 of the Patent Cooperation Treaty. See MPEP 1893.03(f).
Appropriate correction is required.
Specification Objection
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The specification has the following hyperlink on page 17, line 2. Browser-executable code/non-top-level code is bolded for clarity:
https://www.jimmunol.org/content/168/7/3145.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 2, 5, 7, 8, 10, 13, 14, 16- 21, and 23-26, are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0290686 A1 (herein Wickham) in view of Zeng W, et al. (2014) Artificial antigen-presenting cells expressing CD80, CD70, and 4-1BB ligand efficiently expand functional T cells specific to tumor-associated antigens. Immunobiology. 2014 Aug;219(8):583-92 (herein Zeng).
In regard to claims 1, and 4, Wickham teaches an artificial antigen presenting cell, derived from erythroid cell, that is engineered to activate T cells ([0006]). It is disclosed that the engineered cells present on the cell surface at least one antigen presenting peptide (i.e. MHC class I or II), which in certain embodiments is a fusion protein linked to an exogenous antigenic peptide selected from a group consisting of tumor antigens, autoimmune disease antigens, viral antigens, bacterial antigens, or parasite antigens ([0008], [0013], and figure 1). Wickham also teaches that the artificial antigen presenting cell may also further comprise at least one exogenous costimulatory polypeptide (i.e. 4-1BBL, CD86, or CD70), and in certain embodiments may contain up to 5 such peptides ([0014], [1067-1074], figures 9-11).
Wickham does not teach the specific pairing of costimulatory peptides comprising 4-1BBL (CD137L), CD86, and CD70. This deficiency is taught by Zeng.
Zeng teaches K562-derived artificial antigen presenting cells comprised of surface-expressed CD80, CD70, and 4-1BBL co-stimulatory molecule ligands, which were used for the expansion of MART-1-specific T cells (abstract). In this study Zeng explores the effects of co-expressing different combinations of co-stimulatory ligands in order to determine optimal pairings for the generation of efficient “off-the-shelf” artificial antigen presenting cells for use in stimulating functional antigen-specific T cells. Zeng notes that co-stimulation via the CD27/70 interaction has been previously observed to play an important role in efficient T cell responses in multiple animal models (Results: Apoptosis of antigen-specific T cells was accelerated by the CD27/CD70 interaction, but prevented by the 4-1BB/4-1BBL interaction). It is also noted that co-stimulation using CD27/CD70 and CD28/CD80 resulted in suboptimal expansion efficacy, due to a higher-than expected percentage of apoptotic cell in the pentamer-positive CD8+ T cell population (figure 5). It was found that the inclusion of the 4-1BBL ligand and the resulting 4-1BB/4-1BBL co-stimulatory interaction improved expansion by preventing apoptotic cell death.
It would have been obvious to one skilled in the art to combine the teachings of Wickham (an artificial antigen presenting cell expressing a fusion protein comprising a stimulatory ligand and an antigen peptide) and Zeng (an artificial antigen presenting cell expressing co-stimulatory ligands that interact with CD28, CD27, and 4-1BB). One of ordinary skill in the art at the time of filing would have been motivated to incorporate co-expression of co-stimulatory ligands that interact with CD27 (CD70), CD28 (CD80 or CD86), and 4-1BB (CD137L/4-1BBL), due to the recognized benefit of enhanced T cell proliferation as taught by Zeng, with the antigen peptide-stimulatory ligand fusion protein taught by Wickham. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
In regard to claim 2, 8, 13, 14, 16- 18, and 20 Wickham and Zeng teach artificial antigen presenting cells comprising a fusion protein comprised of an immune stimulatory ligand and an exogenous antigen peptide, and co-stimulatory ligands comprising CD70, CD86, and 4-1BBL, see 103 rejection of claims 1 and 4.
Wickham further teaches the combination of ligands is delivered via a lentivirus vector, into which the nucleic acids encoding each ligand are cloned into multiple cloning sites ([1059]). The resulting vector is then used to transduce mammalian cells, erythroid precursor cell ([1058-1060]). The engineered erythroid cells were put into contact with primary CD8+ cells, and were shown to potently and selectively activate the T cell, resulting in the expansion of antigen-specific T cells ([1063-1066] and figures 8a-c).
In regard to claim 19 and 21, Wickham and Zeng teach artificial antigen presenting cells comprising a fusion protein comprised of an immune stimulatory ligand and an exogenous antigen peptide, as well as co-stimulatory ligands comprising CD70, CD86, and 4-1BBL, see 103 rejection of claims 1 and 4.
Wickham teaches the administration of one or more artificial antigen presenting cells, wherein each engineered cell encodes different molecules, and thus expand different populations of antigen-specific immune cells ([0543]).
In regard to claim 5, 7, and 10, Wickham and Zeng teach artificial antigen presenting cells comprising a fusion protein comprised of an immune stimulatory ligand and an exogenous antigen peptide, as well as co-stimulatory ligands comprising CD70, CD86, and 4-1BBL, see 103 rejection of claims 1 and 4.
Wickham provides an example in which the artificial antigen presenting cell comprises PR1 (antigen peptide) fused to the stimulatory ligand HLA A2, an MHC class 1 protein, and the co-stimulatory ligand 4-1BBL ([0987]). These cells were used to stimulate the activation of primary CD8+ T cells ([0993]).
In regard to claims 23 and 24, Wickham and Zeng teach artificial antigen presenting cells comprising a fusion protein comprised of an immune stimulatory ligand and an exogenous antigen peptide, as well as co-stimulatory ligands comprising CD70, CD86, and 4-1BBL, see 103 rejection of claims 1 and 4.
Wickham teaches methods of treating a subject in need of an altered immune response comprising contacting a population of T cells with artificial antigen presenting cells, either in vivo or in vitro, thereby inducing an immune response ([0093-0098], [1048], and [1019-1023]).
In regard to claims 25 and 26, Wickham and Zeng teach artificial antigen presenting cells comprising a fusion protein comprised of an immune stimulatory ligand and an exogenous antigen peptide, as well as co-stimulatory ligands comprising CD70, CD86, and 4-1BBL, see 103 rejection of claims 1 and 4.
Wickham further teaches that the artificial antigen presenting cell may be used to identify or screen antigens for their applicability to vaccine development ([0745]). It is noted that this method involves the ex vivo activation of T cells, collected from a subject and activated through contact with an exogenous stimulatory ligand and co-stimulatory ligand(s). It is also taught that the ELISPOT assay may be used for the detection of T cell activation markers ([1018]). One of ordinary skill in the art would know to combine these teachings to devise a method encompassing the limitations of instant claims 25 and 26.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0290686 A1 (herein Wickham) in view of Zeng W, et al. (2014) Artificial antigen-presenting cells expressing CD80, CD70, and 4-1BB ligand efficiently expand functional T cells specific to tumor-associated antigens. Immunobiology. 2014 Aug;219(8):583-92 (herein Zeng) and Pittet MJ, et al. (2003) Alpha 3 domain mutants of peptide/MHC class I multimers allow the selective isolation of high avidity tumor-reactive CD8 T cells. J Immunol. 2003 Aug 15;171(4):1844-9 (herein Pittet).
Wickham and Zeng teach artificial antigen presenting cells comprising a fusion protein comprised of an immune stimulatory ligand and an exogenous antigen peptide, as well as co-stimulatory ligands comprising CD70, CD86, and 4-1BBL, see 103 rejection of claims 1 and 4.
Wickham and Zeng do not teach an immune stimulating molecule with attenuated CD8 affinity. This deficiency is taught by Pittet.
The teachings of Pittet probe the interplay between CD8 binding to pMHC molecules and the stability of T cell receptor/pMHC interactions (Introduction). Pittet teaches that there is relationship between T cell functional avidity, towards a specific pMHC ligand, and the level to which the TCR/pMHC interaction depends on cooperative CD8 binding (Introduction). Pittet teaches that T cells capable of binding pMHC independent of CD8 binding possess a higher functional avidity than those that have a higher CD8-dependence (Discussion). This finding is supported by the significantly higher tumor cell lysis capability of T cell clones capable of binding pMHC multimer with ablated CD8 binding, via D227T and K228A mutations in the α3 domain of the HLA-A2 H chain, compared to lysis levels of T cells requiring CD8 binding (Results: Ex vivo identification, isolation, and characterization of Melan-A/227,8KA-A2 multimer+ cells in healthy individuals and melanoma patients and figure 3).
It would have been obvious to one skilled in the art to combine the teachings of Wickham (an artificial antigen presenting cell expressing a fusion protein comprising a stimulatory ligand and an antigen peptide) and Zeng (an artificial antigen presenting cell expressing co-stimulatory ligands that interact with CD28, CD27, and 4-1BB) with the teaching of Pittet (the use of an immune stimulatory ligand with attenuated CD8 binding). One of ordinary skill in the art at the time of filing would have been motivated to design an artificial antigen presenting cell with an immune stimulatory ligand with attenuated CD8 binding, due to the recognized benefit of selectively activating and expanding T cell populations with high functional avidity, as taught by Pittet. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
Conclusion
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647