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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 4/13/2026 is acknowledged.
Claims 1-6, 8, 11, 14, 17, 21, 24-26, 28-29, 32-33 and 35 are currently pending.
Claims 29, 32-33 and 35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/13/2026.
Claims 1-6, 8, 11, 14, 17, 19, 21, 24-26 and 28 will be examined on the merits.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located:
Claim 14—Claim 14 recites SEQ ID NOs: 73-78 but the Sequence Listing only goes up to SEQ ID NO: 54.
Note: The objection to claim 54 is because of this issue
Specification—The Specification recites SEQ ID NOs: 73-78 on pages 4 and 42 but the sequence listing only goes up to SEQ ID NO: 54.
Note: The objection to the Specification is because of this issue.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 17 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 17 recites the limitations "the processable linker", “the MHC class II alpha chain” and “the MHC class II component” in the body of the claim. There is insufficient antecedent basis for all of these limitations in the claim.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-5, 21 and 24-25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Moriarity (Moriarity, et al., US 2019/0008899A1; Published 1/10/2019).
Moriarity teaches methods of using CRISPR technology (Moriarity, Abstract). Regarding claim 1, Moriarity teaches of a phase I trial for TIL therapy for GI Cancer (Moriarity, ¶ 0303) wherein: a) subjects with GI cancer underwent surgical resection of tumorous samples and TILs were grown and expanded (satisfying step “a”) (Moriarity, ¶ 0303), b) an aliquot of the original tumor sample is subject to exomic sequencing (satisfying step “b”; also satisfies claims 2-3) (Moriarity, ¶ 0303), c) the TILs were then pulsed with APC cells presenting 25-mer peptides, including the mutated peptide) (thus satisfying step “d”; also , binding to APCs means HLA binding status was determined for the neoantigen, thus satisfying “c”) (Moriarity, ¶ 0303), and d) that the TIL cultures shown to have demonstrated mutation-recognition are sent to a GMP cell production facility where the TILs are subject to CRISPR genomic knockout and successful populations being further expanded and then cryopreserved for patient use (thus satisfying “e”) (Moriarity, ¶ 0303). Regarding claim 4, Moriarity teaches that in the method of Moriarity an aliquot of tumor is subject to exomic sequencing and, when possible, transcriptome sequencing to identify mutations uniquely present in cancer cells compared to normal cells (Moriarity, ¶ 0303). Regarding claim 5, Moriarity teaches that the patient-specific mutations are identified by exomic sequencing (Moriarity, ¶ 0303) and all mutations identifiable by exomic sequencing are point mutations, splice site mutations, frameshift mutations, read-through mutations, fusions, insertion or deletions; regarding the HLA binding limitation of claim 5, Moriarity teaches that the mutated peptides are presented to TILs by antigen-presenting cells (Moriarity, ¶ 0303) and only HLA-binding peptides bind APCs. Regarding claim 21, Moriarity teaches that the TILs of Moriarity are genetically engineered to knock out PD-1 and CTLA-4 (Moriarity, ¶ 0299-0300). Regarding claim 24, Moriarity teaches intralymphatic injection of the therapeutic expanded TILs of Moriarity (Moriarity, ¶ 0273). Regarding claim 25, Moriarity teaches that the cells expanded at the GMP facility (same as the second expansion of Moriarity; see ¶ 0303) were supplemented with IL-2 (Moriarity, ¶ 0397).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-6, 14, 21 and 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over by Moriarity (Moriarity, et al., US 2019/0008899A1; Published 1/10/2019) as applied to claims 1-5, 21 and 24-25 above and in further view of Wucherpfenning, (Wucherpfenning, et al., WO 2004/007528 A1; Published 1/22/2005) and CD Genomics (CD Genomics, et al., Overview of HLA typing; First Published 1/27/2021; URL = https://www.cd-genomics.com/an-overview-of-hla-typing.html; Accessed 5/6/2026).
The teachings of Moriarity are discussed above.
Moriarity does not teach that the binding between neoantigens and HLA proteins in the TILs is determined by: a) culturing a cell transformed with at least one nucleic acid molecule encoding: I) a MHC component comprising at least a portion of a MHCII alpha chain and at least a portion of a MHC II beta chain such that the alpha and beta chains form a peptide binding grove and II) a spaceholder molecule and a first processable linker, wherein the spaceholder is linked to the MHCII component by the processible linker and the spaceholder binds within the peptide binding groove, thereby hindering the binding of any other peptide, b) recovering the MHCII component, c) processing the processable linker, thereby releasing the spaceholder from the peptide binding groove, d) incubating the MHCII component in the presence of a neoantigen, wherein the incubation facilitates the binding of the neoantigen to the peptide binding groove and e) recovering the MHCII component that has bound the neoantigen. Moriarity does not teach that the method of Moriarity comprises MHC genotyping of the patient.
Wucherpfenning teaches on the subject of novel MHC II compounds, methods of generating such compounds as well as methods useful in identifying antigen-specific T cells (Wucherpfenning, Abstract). Wucherpfenning teaches a method of producing MHC II compounds comprising the steps of: a) culturing a cell transformed with at least one nucleic acid molecule encoding: I) a MHC component comprising at least a portion of a MHCII alpha chain and at least a portion of a MHC II beta chain such that the alpha and beta chains form a peptide binding grove and II) a spaceholder molecule and a first processable linker, wherein the spaceholder is linked to the MHCII component by the processible linker and the spaceholder binds within the peptide binding groove, thereby hindering the binding of any other peptide, b) recovering the MHCII component, c) processing the processable linker, thereby releasing the spaceholder from the peptide binding groove, d) incubating the MHCII component in the presence of a antigenic peptide, wherein the incubation facilitates the binding of the antigenic peptide to the peptide binding groove and e) recovering the MHCII component that has bound the antigenic peptide (Wucherpfenning, p 9, lines 1-16). Wucherpfenning also teaches that the MHC II compounds produced by the method of Wucherpfenning are used in methods of identifying antigen-specific T cells, comprising the steps of culturing a MHC II compound produced by the method of Wucherpfenning with at least one isolated T cell to form a MHC II-T cell complex, which is isolated and then assayed (Wucherpfenning, p 9, lines 21- 26).
CD genomics teaches that all HLA molecules are encoded in the HLA region of chromosome 6 (CD Genomics, p 2, Fig. 1), and that HLA typing by next generation sequencing of the complete HLA region of chromosome 6 for the purposes of HLA I and HLA II molecular polymorphism detection (same as patient genotyping of HLA I and II; CD Genomics, p 4, Fig. 3; p 5, ¶ 2-3) and that these techniques have been known in the art since at least 2001 (CD Genomics, Cover Sheet).
It would be prima facie obvious to one of ordinary skill in the art to apply the MHCII compound generation/binding identification method of Wucherpfenning to the method of TIL identification and production taught by Moriarity. The net result of this application would be the method of identifying TILs of Moriarity, wherein the specific binding between the neoantigens and a MHC protein is identified by the method of Wucherpfenning, said method comprising: a) culturing a cell transformed with at least one nucleic acid molecule encoding: I) a MHC component comprising at least a portion of a MHCII alpha chain and at least a portion of a MHC II beta chain such that the alpha and beta chains form a peptide binding grove and II) a spaceholder molecule and a first processable linker, wherein the spaceholder is linked to the MHCII component by the processible linker and the spaceholder binds within the peptide binding groove, thereby hindering the binding of any other peptide, b) recovering the MHCII component, c) processing the processable linker, thereby releasing the spaceholder from the peptide binding groove, d) incubating the MHCII component in the presence of a neoantigenic peptide of Moriarity, wherein the incubation facilitates the binding of the neoantigenic peptide of Moriarity to the peptide binding groove and e) recovering the MHCII component that has bound the neoantigenic peptide of Moriarity. One of ordinary skill in the art would be motivated to do this in order to identify the specific MHC molecules bound by the neoantigens of Moriarity. Moriarity teaches that neoantigenic peptides are bound to APCs in the method of TIL identification/production of Moriarity but does not specifically teach how to identify which MHC molecules on the APCs the neoantigens of Moriarity bind to. The method of Wucherpfenning fills this void by providing a known method of identifying which specific MHCII molecule(s) any given neoantigenic peptide binds to. One of ordinary skill in the art would have a reasonable expectation of success applying the MHCII compound generation/binding identification method of Wucherpfenning to the method of TIL identification and production taught by Moriarity because Moriarity teaches binding of neoantigenic peptides to APCs but does not teach a specific method of identifying which MHC molecules (present on the APCs) each of the neoantigen(s) bind(s) to and Wucherpfenning provides a known, specific method of determining specific binding between any given neoepitope and any given MHC II alpha and beta pairing.
It would be prima facie obvious to one of ordinary skill in the art to further modify the combined method of Moriarity and Wucherpfenning discussed above to further comprise performing the HLA typing of CD Genomics on the patient. One of ordinary skill in the art would be motivated to do this in order to match the neoantigens identified as binding MHCII molecules using the method of Wucherpfenning with the patient’s specific MHCII genotype. One of ordinary skill in the art would have a reasonable expectation of success further modifying the combined method of Moriarity and Wucherpfenning discussed above to further comprise performing the HLA typing of CD Genomics on the patient because CD genomics teaches that HLA typing was an established method to determine the specific molecular polymorphism of a patient’s MHC I and II molecules that has been routine in the art since 2001.
Claim(s) 1-5, 21 and 24-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over by Moriarity (Moriarity, et al., US 2019/0008899A1; Published 1/10/2019) as applied to claims 1-5, 21 and 24-25 above and in further view of Li (Li. Et al., Cryotherapy 2019 21(1):76).
The teachings of Moriarity are discussed above.
To reiterate, Moriarity teaches that the cells expanded at the GMP facility (same as the second expansion of Moriarity; see ¶ 0303) were supplemented with IL-2 (Moriarity, ¶ 0397).
Moriarity does not teach that the second expansion of TILs takes place in a closed reactor comprising a gas permeable membrane, wherein the cells are expanded at least 50-fold.
Li teaches of a closed loop bioreactor specifically for T cell proliferation, said reactor comprising a highly gas permeable silicone material and dynamic flow to dissociate activated T cell aggregates (Li, Abstract). Li teaches that the closed loop bioreactor of Li produced ~ 75-fold increase in T cell population at day 9 of fermentation, compared to a ~50-fold increase in T cells for a shake flask (Li, p 12, Fig. 3).
It would be prima facie obvious to one of ordinary skill in the art to combine the IL-2 supplemented T cell expansion of Moriarity with the closed loop bioreactor comprising a gas permeable loop of Li. The net result of this combination would be a method wherein the second TIL expansion of Moriarity takes place in the closed loop bioreactor of Li in the presence of the IL-2 of Moriarity. One of ordinary skill in the art would be motivated to do this in order to perform the TIL expansion in a known bioreactor designed for T cell expansion. One of ordinary skill in the art would have a reasonable expectation of success performing the second expansion of Moriarity in the presence of the IL-2 of Moriarity in the closed loop bioreactor of Li because Li teaches the closed loop bioreactor of Li is specifically designed for T cell expansion and outperformed shake flasks by 25-fold in terms of T cell population. One of ordinary skill in the art would also reasonably expect at least 50-fold T cell expansion because Li teaches the bioreactor of Li produced 75-fold T cell expansion.
Claim(s) 1-5, 8, 11, 21 and 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over by Moriarity (Moriarity, et al., US 2019/0008899A1; Published 1/10/2019) as applied to claims 1-5, 21 and 24-25 above and in further view of Dogan (Dogan Eur. J. Immunol. 2004 34:598) and Zimmerman (Zimmerman, et al., Drug Discov Today 2016 21(11):1828).
The teachings of Moriarity are discussed above.
Moriarity does not teach that the identification of neoantigens binding MHC molecules comprises the steps of: 1) generating a combinatorial library of polypeptides with phage display, wherein each peptide comprises a peptide portion and an identifying nucleic acid portion, 2) contacting the combinatorial library with HLA proteins, 3) separating the HLA proteins demonstrating specific binding, and 4) sequencing the identifying nucleic acid portion of the peptides capable of specific binding to HLA proteins.
Dogan teaches an original phage-displayed library of noncovalent complexes of peptides and MHC molecules (Dogan, Abstract). Dogan teaches that soluble MHC molecules associate with peptides presented by a phage, resulting in peptide/MHC/phage complexes, which were then screened for binding using monoclonal antibody 25D (Dogan, Abstract).
Zimmerman teaches that DNA-encoded chemical libraries comprise a link between the displayed chemical building block linked an amplifiable DNA “barcode”, which are then screened by PCR amplification of the genetic “barcodes”, allowing for screening of vast libraries in a single test tube (Zimmerman, Abstract).
It would be prima facie obvious to one of ordinary skill in the art to combine the TIL expansion method of Moriarity with the phage display peptide/MHC library screening method of Dogan and the DNA “barcoding” of Zimmerman. The net result of this combination would be the method of Moriarity wherein the candidate peptides are screened for MHC binding using the phage display method of Dogan and positive complexes are identified using the DNA “barcode” screening method of Zimmerman. One of ordinary skill in the art would be motivated to do this in order to have a high throughput method of testing candidate MHC-binding neoantigens as well as a high throughput method of screening/detecting candidate MHC-binding neoantigens. One of ordinary skill in the art would have a reasonable expectation of success to combining the TIL expansion method of Moriarity with the phage display peptide/MHC library screening method of Dogan and the DNA “barcoding” of Zimmerman because: 1) Dogan teaches that phage libraries comprising candidate epitopic peptides expressed on phages as a viable method for screening large libraries of candidate epitopic peptides for MHC binding and 2) the DNA “barcoding” tag technique taught by Zimmerman allows for high throughput detection of bound species without having the requirement of needing an antibody (such as antibody 25D of Dogan) to screen for positive binding peptides.
Claim(s) 1-5, 19, 21 and 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over by Moriarity (Moriarity, et al., US 2019/0008899A1; Published 1/10/2019) as applied to claims 1-5, 21 and 24-25 above and in further view of Kurokawa (Kurokawa, et al., Immunol Lett 2002 p 163) and DTU (DTU NetMHCpan-4.1; First available 4/24/2020; URL = https://services.healthtech.dtu.dk/services/NetMHCpan-4.1/; Accessed 5/6/2026)
The teachings of Moriarity are discussed above.
Moriarity does not teach that the specific binding between the neoantigens and HLA proteins is determined by phage display, wherein the HLA proteins are expressed on the phage surface and are incubated with neoantigens to assay specific binding. Moriarity. Moriarity does not teach that the method of determining specific binding further comprises in silico analysis applying a computational algorithm to predict MHC binding.
Kurokawa teaches of single chain class I MHC molecules expressed on the surface of filamentous phages and that the expressed scMHCI, phage bound MHCI molecules are able to form complexes with antigenic peptides (Kurokawa, Abstract) and the expressed scMHC-I of the MHCI phage library of Kurokawa was found to bind peptides of the correct specific binding motif (Kurokawa, p 167, ¶ 4; Fig. 2c).
Danmarks Tekniske Universitet (DTU) teaches that NetMHCpan4.1 was a pan-specific algorithm capable of predicting the binding of peptides to any MHC molecule of known sequences (DTU, p 1, ¶ 1) and that this technology was available as of 4/24/2020 (DTU, Cover Sheet).
It would be prima facie obvious to one of ordinary skill in the art
to modify the method of TIL expansion of Moriarity with the phage display MHC library screening method taught by Kurokawa and the NETMHCspan4.1 algorithm taught by DTU. The net result of this combination would be the method of TIL expansion taught by Moriarity wherein the specific binding between the peptides and MHC molecules is determined by screening the candidate peptides vs the scMHCI library of Kurokawa to identify MHCI binding peptides and specific binding of identified MHCI-binding peptides being determined using the NETMHCspan4.0 algorithm of Moriarity. One of ordinary skill in the art would be motivated to do this in order perform high throughput screening, testing and identification with respect to MHCI-candidate neoantigen binding. One of ordinary skill in the art would have a reasonable expectation of success to modifying the method of TIL expansion of Moriarity with the phage display MHC library screening method taught by Kurokawa and the NETMHCspan4.1 algorithm taught by DTU because the method of Kurokawa provides a method to screen a large number of candidate antigens vs a MHCI phage library to identify MHCI binders and the NETMHCspan4.0 algorithm of DTU allows for rapid determination of which specific MHCI molecule the binding antigenic peptides are likely to bind to.
Claim(s) 1-5, 21, 24-25 and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over by Moriarity (Moriarity, et al., US 2019/0008899A1; Published 1/10/2019) as applied to claims 1-5, 21 and 24-25 above and in further view of New England Biolabs (NEB) (NEB, et al., Protocol for Preparation of Frozen Stock; First available 11/20/2005; URL = https://www.neb.com/en-us/protocols/protocol-for-preparation-of-frozen-stock?srsltid=AfmBOopof8k3cIOmwHjb4AKojZ0CQJEEVF4csIHEFfL_9EmenutWw1Un; Accessed 5/6/20206) as evidenced by Aswad (Aswad, et al., BMC Biotechnology 2016 16:32) and ThermoFisher (ThermoFisher, et al., The Basics of Fetal Bovine Serum Use in Cell Culture; First available 6/26/2023; URL = -cell-culture-basics/cell-culture-environment/fbs-basics.html; Accessed 5/13/2026)
The teachings of Moriarity are discussed above.
Moriarity does not teach a cryopreserved composition of TILs comprising a cryoprotectant medium comprising DMSO, an electrolyte, one or more stabilizers and one or more lymphocyte growth factors.
NEB teaches a protocol for preparation of frozen mammalian cell cultures comprising freezing the cells at -70C in a cryoprotectant medium comprising DMEM, FBS and DMSO (NEB, p 1). As evidenced by ThermoFisher, the FBS of NEB comprises bovine serum albumin (a stabilizer) as a major component (ThermoFisher, page 2), as evidenced by Aswad, the FBS of NEB comprises the lymphocyte growth factor IL6 (Aswad, Fig. 6) and electrolytes (any compound that dissociates into ions) are ubiquitous in biological systems.
It would be prima facie obvious to one of ordinary skill in the art to store the TILs of Moriarity using the cryopreservation protocol of NEB. One of ordinary skill in the art would be motivated to do this in order to store the TILs of Moriarity at -70C for long-term storage. One of ordinary skill in the art would have a reasonable expectation of success storing the TILs of Moriarity using the cryopreservation protocol of NEB because NEB teaches that the protocol of NEB is for storage of mammalian cell cultures.
Claim(s) 1-5, 21, 24-25 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over by Moriarity (Moriarity, et al., US 2019/0008899A1; Published 1/10/2019) as applied to claims 1-5, 21 and 24-25 above and in further view of Yang (Yang, et al., Gastroentrol Report 2018 6(4):243).
The teachings of Moriarity are discussed above.
Moriarity does not teach the method of Moriarity further comprising performing an immune infiltration assay with organoids derived from patient tumor cells to confirm enhanced infiltration of the organoids with the second population of TILs compared to the first.
Yang teaches patient-derived organoids as a model for personalized cancer treatment (Yang, title). Yang teaches that tumor organoids as a model for identifying and testing novel cancer drugs (Yang, p 243, ¶ 3). Yang teaches that patient-derived tumor organoids (PDO) are embedded in a 3D matrix to mimic an extracellular matrix and are then used to test large numbers of candidate drugs, with PDO-based screening having an accuracy of 88% for predicting if a patient would respond to a drug and 100% accuracy for predicting if a patient would not respond to a drug (Yang, p 243, ¶ 3). Yang also teaches that PDOs may be used to assess the efficiency of T-cell mediated tumor killing (Yang, p 245, ¶ 1).
It would be prima facie obvious to combine the method of TIL production taught by Moriarity with the PDO-based T-cell mediated killing assay taught by Yang. The net result of this combination would be the method of Moriarity wherein the PDO-based T-cell mediated killing assay of Yang is performed to verify efficient T-cell based killing of tumor cells expanded according to the method of Moriarity. One of ordinary skill in the art would be motivated to do this in order to verify the anticancer efficacy of the TILs produced by the method of Morarity. One of ordinary skill in the art would have a reasonable expectation of success combining the method of TIL production taught by Moriarity with the PDO-based T-cell mediated killing assay taught by Yang because Yang teaches that PDO-based assays are capable of assessing T-cell mediated tumor killing and because Yang teaches that PDO-based assays are 88% accurate with respect to identifying positives and 100% accurate in identifying negatives.
Conclusion
Claims 1-6, 8, 11, 14, 17, 19, 21, 24-26 and 28 are rejected.
Claim 14 is objected to.
The Specification is objected to.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sydney Van Druff whose telephone number is (571)272-2085. The examiner can normally be reached 10 am - 6 pm.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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