DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 13 August 2025 has been entered.
Status of the Claims
Applicant’s submission filed 13 August 2025 has been entered. Claims 33-41 are pending. Claim 33 has been amended, with support for the amendment found on Pages 41-42 of the instant Specification filed 17 December 2024. Therefore, claims 33-41 remain pending for examination on the merits as being drawn to the elected invention. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Nucleotide and/or Amino Acid Sequence Disclosures
Applicant has traversed the rejection, asserting in Pages 4-5 of the Remarks filed 13 August 2025 that an Incorporation by Reference paragraph is not required under 37 CFR § 1.821(c)(1) since the instant application is a national stage entry under § 1.495(b)(1), and the ‘Sequence Listing’ has been previously communicated by the International Bureau or originally filed in the United States Patent and Trademark Office and complies with Patent Cooperation Treaty (PCT) Rule 5.2. In response, the Examiner respectfully submits that the sequence disclosure provided in the national stage entry only discloses the sequences for instant SEQ ID NOs: 1-5. See, for example, Pages 70-75 of the certified copy of PCT/EP2020/056086 made available under the Patent Cooperation Treaty and entered into the application file on 01 September 2021. Therefore, the ‘Sequence Listing’ provided within the national stage entry is not compliant with 37 CFR § 1.821(c)(1), as instant SEQ ID NO: 6 is not provided within any part of that disclosure.
Therefore, the objection Specification in regards to the nucleotide and/or amino acid sequence disclosures is maintained.
RE: Rejection of claim 41 under 35 USC 112(b)
Applicant’s amendments to instant claim 41 in the claim set filed 09 June 2025, which were entered in the Office action filed 23 June 2025, clarifies the claim scope and removes the exemplary language, thus obviating the current rejections of record.
Therefore, the rejections are withdrawn.
RE: Rejection of claims 33-37 under 35 USC 102(a)(1) and 35 USC 102(a)(2) over Liang et al as evidenced by Das et al and Bardal et al
Applicant’s amendment to independent claim 33 requiring the cancer to be “selected from the group consisting of colorectal cancer, brain cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, renal cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, oral cancer, head and neck cancer, esophageal cancer, gastric cancer, cervical cancer, bladder cancer, lymphoma, chronic or acute leukemia, sarcoma, lung cancer and multidrug resistant cancer” obviates the current rejection of record, as it is a new limitation that has not been previously considered by the Examiner.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 33-40 under 35 USC 103 over Liang et al as evidenced by Das et al and Bardal et al, and further in view of Meissner et al
Applicant’s amendment to independent claim 33 requiring the cancer to be selected from the group consisting of colorectal cancer, brain cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, renal cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, oral cancer, head and neck cancer, esophageal cancer, gastric cancer, cervical cancer, bladder cancer, lymphoma, chronic or acute leukemia, sarcoma, lung cancer and multidrug resistant cancer obviates the current rejection of record, as it is a new limitation that has not been previously considered by the Examiner.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 33-40 under 35 USC 103 over Liang et al as evidenced by Das et al and Bardal et al, and further in view of Meissner et al and Frost et al
Applicant’s amendment to independent claim 33 requiring the cancer to be selected from the group consisting of colorectal cancer, brain cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, renal cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, oral cancer, head and neck cancer, esophageal cancer, gastric cancer, cervical cancer, bladder cancer, lymphoma, chronic or acute leukemia, sarcoma, lung cancer and multidrug resistant cancer obviates the current rejection of record, as it is a new limitation that has not been previously considered by the Examiner.
Therefore, the rejection is withdrawn.
New/Maintained Grounds of Rejection
Nucleotide and/or Amino Acid Sequence Disclosures
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/patents-application- process/filing-online/legal-framework-efs-web), 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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must 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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 33-37 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al (WO 2016/025454 A2, of record) as evidenced by Bardal et al (Applied Pharmacology, 2011, of record), and in view of Das et al (JEM, 2013, of record) and Kalal et al (Onco Rev, 2017).
Regarding claims 33 and 35-36: Liang et al disclose T cells expressing receptors that that cause a cell expressing the receptor to home to specific anatomical regions, such as the skin, as well as methods of using the T cells to treat cancer (Abstract).
As such, Liang et al disclose primary human T lymphocytes genetically modified to comprise a CCR8 skin homing receptor. With that, Liang et al disclose that the CCR8 polypeptide expressed within the genetically engineered human T lymphocytes is provided in GenBank™ accession number NP 005192.1 (Paragraphs [0004], [0036]).
Liang et al further disclose that the CCR8-genetically modified human T lymphocytes are administered to patients suffering from skin cancer, including melanoma (Paragraph [0042]).
Liang et al do not disclose that the cancer is a multidrug resistant cancer characterized by the expression of CCL1 within the tumor parenchyma or characterized by comprising CCL1 expressing tumor resident immune cells, as required by instant claim 33.
Das et al, however, disclose that melanoma tumors occasionally express CCL1 within the tumor parenchyma (Das et al, Page 1517, CCL1 is expressed…).
With that, Kalal et al disclose that malignant melanoma is a multidrug resistant cancer, as it resists various chemotherapeutics and cytostatic drugs (Pages 19-21; Table 1).
Therefore, it would have been prima facie obvious to have modified the method of Liang et al such that the CCR8-genetically modified human T lymphocytes are administered to patients suffering from CCL1-expressing melanoma tumors, as detailed in Das et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to administer the CCR8-genetically modified human T lymphocytes of Liang et al to subjects suffering from multidrug-resistant, CCL-1 expressing melanoma, as Kalal et al disclose that targeted therapies and immunotherapies can overcome the drug resistance (Pages 21-22), and would have had a reasonable expectation of success given that Liang et al disclose the administration of CCR8-genetically modified human T lymphocytes to patients suffering from melanoma. See MPEP § 2143(I)(G).
Consequently, Liang et al as modified by Das et al and Kalal et al render obvious the treatment of melanoma in an individual, wherein primary human T lymphocytes (claim 36) are genetically engineered to express a CCR8 polypeptide provided in GenBank™ accession number NP 005192.1. This CCR8 accession number has 100% sequence identity to instant SEQ ID NO: 1 (claim 35; see sequence alignment below). As melanoma is a multidrug resistant cancer, and the tumors are found to express CCL1 within the tumor parenchyma, this therefore reads on the method of instant claim 33.
Query Match 100.0%; Length 355; Matches 355; Gaps 0
Qy 1 MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNGKLLLAVFYCLLFVFSLLGNSLVILVL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNGKLLLAVFYCLLFVFSLLGNSLVILVL 60
Qy 61 VVCKKLRSITDVYLLNLALSDLLFVFSFPFQTYYLLDQWVFGTVMCKVVSGFYYIGFYSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VVCKKLRSITDVYLLNLALSDLLFVFSFPFQTYYLLDQWVFGTVMCKVVSGFYYIGFYSS 120
Qy 121 MFFITLMSVDRYLAVVHAVYALKVRTIRMGTTLCLAVWLTAIMATIPLLVFYQVASEDGV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 MFFITLMSVDRYLAVVHAVYALKVRTIRMGTTLCLAVWLTAIMATIPLLVFYQVASEDGV 180
Qy 181 LQCYSFYNQQTLKWKIFTNFKMNILGLLIPFTIFMFCYIKILHQLKRCQNHNKTKAIRLV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LQCYSFYNQQTLKWKIFTNFKMNILGLLIPFTIFMFCYIKILHQLKRCQNHNKTKAIRLV 240
Qy 241 LIVVIASLLFWVPFNVVLFLTSLHSMHILDGCSISQQLTYATHVTEIISFTHCCVNPVIY 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LIVVIASLLFWVPFNVVLFLTSLHSMHILDGCSISQQLTYATHVTEIISFTHCCVNPVIY 300
Qy 301 AFVGEKFKKHLSEIFQKSCSQIFNYLGRQMPRESCEKSSSCQQHSSRSSSVDYIL 355 (SEQ ID NO: 1)
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 AFVGEKFKKHLSEIFQKSCSQIFNYLGRQMPRESCEKSSSCQQHSSRSSSVDYIL 355 (NP 005192.1)
Regarding claim 34: Following the discussion of claim 33, Liang et al further disclose that the T lymphocytes are allogeneic to an individual to whom the T lymphocytes are to be administered (Paragraph [0066]). This therefore reads on the method of the instant claim.
Regarding claim 37: As aforementioned in the discussion of claim 33, Liang et al disclose that the primary human lymphocytes are T lymphocytes (Paragraph [0065]). As CD3 is the defining marker for T lymphocytes, the primary human T lymphocytes will inherently be CD3+ (Bardal et al, Page 1). This therefore reads on the method of the instant claim.
Claims 33-40 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al (WO 2016/025454 A2, of record) as evidenced by Bardal et al (Applied Pharmacology, 2011, of record), and in view of Das et al (JEM, 2013, of record) and Kalal et al (Onco Rev, 2017), and further in view of Meissner et al (US 2019/0309259 A1, of record).
The discussion of Liang et al as modified by Das et al and Kalal et al regarding claim 33 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Liang et al as evidenced by Bardal et al and as modified by Das et al and Kalal et al render obvious claims 33-37. Meissner et al is considered prior art under 35 USC 102(a)(2), with a priority date of 09 May 2016.
Regarding claims 38-39: Following the discussion of claim 33, Liang et al further disclose that
the T lymphocytes are allogenic MHC-restricted T lymphocytes that limit graft-versus-host disease
(GVHD) in the individual (Paragraphs [0065]-[0066]).
Liang et al further disclose that the CCR8-genetically modified human T lymphocytes also comprise genetic modifications to reduce or eliminate expression of the native genes encoding TCR-α and TCR-β (Paragraph [0068]).
The combination of Liang et al, Das et al, and Kalal et al do not teach that the T lymphocytes are non-alloreactive, as required in instant claim 38.
Meissner et al, however, disclose universal primary donor T cells for use in cancer immunotherapy that are devoid of MHC-I, MHC-II, and/or TCR surface expression, thereby rendering the cells hypoimmunogenic (Abstract; Paragraphs [0059], [0067], [0078], [00327]-[0328], [00358], [00368]). Meissner et al define “hypoimmunogenic” to mean that a cell is less prone to immune rejection by a subject into which such cells are transplanted. For instance, relative to an unaltered wild-type cell, such a hypoimmunogenic cell may be about 99% or more less prone to immune rejection by a subject into which such cells are transplanted (Paragraph [0180]).
Therefore, it would have been prima facie obvious to modify the method of Liang et al in view of Das et al and Kalal et al such that the primary human T lymphocytes are universal – or non-alloreactive – primary human T lymphocytes, as detailed in Meissner et al. One of ordinary skill before the effective filing date of the invention would have been motivated to utilize primary T lymphocytes that effectively eliminate the possibility of an adverse immune response, and would have had a reasonable expectation of success based on the disclosure of Meissner et al. See MPEP § 2143(I)(G).
Consequently, Liang et al as modified by Das et al, Kalal et al, and Meissner et al render obvious a method of treating cancer, wherein the primary human T lymphocyte is a universal primary human T lymphocyte that lacks surface expression of the native TCR-α and TCR-β genes (claim 39), as well as MHC-I and/or MHC-II. As “universal” and “non-alloreactive” are synonymous – see instant Specification, Page 8 – this therefore renders obvious the method of instant claim 38.
Regarding claim 40: Following the discussion of claim 39, Liang et al further disclose that the primary human T lymphocytes genetically modified to comprise a CCR8 skin homing receptor are further transformed with a polynucleotide encoding a chimeric antigen receptor (Paragraphs [0044], [0057], [0067], [0072]). This therefore renders obvious the method of the instant claim for the same reasons as discussed in instant claims 38-39.
Claims 33-41 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al (WO 2016/025454 A2, of record) as evidenced by Bardal et al (Applied Pharmacology, 2011, of record), and in view of Das et al (JEM, 2013, of record), Kalal et al (Onco Rev, 2017), and Meissner et al (US 2019/0309259 A1, of record), and further in view of Frost et al (WO 2020/047527 A2, of record).
The discussion of Liang et al as modified by Das et al and Kalal et al regarding claim 33 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. The discussion of Liang et al as modified by Das et al, Kalal et al, and Meissner et al regarding claims 38-40 can also be observed above and is relied upon herein, the content of which is incorporated in its entirety. Liang et al as evidenced by Bardal et al and as modified by Das et al and Kalal et al render obvious claims 33-37. Liang et al as evidenced by Bardal et al and as modified by Das et al, Kalal et al, and Meissner et al render obvious claims 33-40. Frost et al is considered prior art under 35 USC 102(a)(2), with a priority date of 02 September 2018.
Regarding claim 41: Following the discussion of claim 40, Liang et al further disclose that the extracellular domain of the chimeric antigen receptor binds to an antigen of interest, wherein the
antigen of interest is a cytokine (Paragraphs [0048], [0055]).
The combination of Liang et al as evidenced by Bardal et al, Das et al, Kalal et al, and Meissner et
al fail teach that the universal primary human T lymphocyte is further engineered to express a modified cytokine receptor that is dominant-negative TGF-β receptor 2, as is required by instant claim 41.
Frost et al, however, disclose methods for genetically modifying T lymphocytes obtained from the blood of human subjects suffering from cancer, wherein the genetic modification involves inserting a polynucleotide encoding a CAR and a cytokine receptor lymphoproliferative element into the T lymphocytes. Frost et al further disclose that the cytokine receptor lymphoproliferative element is TGFβ decoy receptor, or dominant-negative TGF-β receptor 2 (Abstract; Paragraphs [0096]-[0097], [0118]-[0119], [0128], [0132], [0194]-[0199], [0294]-[0295]).
Therefore, it would have been prima facie obvious to further modify the method of Liang et al as modified by Das et al, Kalal et al, and Meissner et al such that the CCR8-genetically modified primary human T lymphocytes comprising CARs are further modified to comprise a dominant-negative TGF-β receptor 2 lymphoproliferative element, as detailed in Frost et al. One of ordinary skill before the effective filing date of the invention would have been motivated to utilize genetically engineered primary T lymphocytes that remove the need to proliferate the T cells in vitro prior to administering them to lymphodepleted subjects, such as those receiving adoptive T cell therapy, and would have had a reasonable expectation of success based on the disclosure of Frost et al (Paragraphs [0242]-[0244]). See MPEP § 2143(I)(G).
Consequently, Liang et al as evidenced by Bardal et al and as modified by Das et al, Kalal et al, Meissner et al, and Frost et al render obvious a method of treating cancer, wherein the CCR8-genetically modified primary human T lymphocytes comprising CARs are further modified to comprise a modified cytokine receptor that is dominant-negative TGF-β receptor 2. This therefore renders obvious the method of the instant claim.
Claims 33-40 are rejected under 35 U.S.C. 103 as being unpatentable over Jakobovits et al (US 2016/0175358 A1, of record on IDS filed 01 September 2021) in view of Liang et al (WO 2016/025454 A2, of record) and Kuehnemuth et al (BMC Cancer, 2018).
Jakobovits et al and Liang et al are each considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2). Kuehnemuth et al is considered prior art under 35 USC 102(a)(1).
Regarding claims 33 and 35-37: Jakobovits et al disclose methods of using engineered primary γδ T-cells as a therapeutic for the treatment of cancer, wherein the cancer is breast cancer (Abstract; Paragraphs [0003], [0011], [0032], [0034], [0043], [0050], [0111]-[0115], [0124], [0131]-[0132]).
As such, Jakobovits et al disclose that the γδ T-cells are engineered to express homing receptors, including CCR8 (Paragraph [0071]).
Jakobovits et al do not disclose that the CCR8 polypeptide has the amino acid sequence set forth in instant SEQ ID NO: 1, as required by instant claim 33.
Liang et al, however, disclose primary human T lymphocytes genetically modified to comprise a CCR8 homing receptor having the amino acid sequence provided in GenBank™ accession number NP 005192.1 (Paragraphs [0004], [0036]).
Therefore, it would have been prima facie obvious to have substituted the CCR8 polypeptide sequence of Jakobovits et al with the CCR8 polypeptide sequence of Liang et al, as doing so would have been a simple substitution of one known CCR8 polypeptide sequence for another. See MPEP § 2143(I)(B). One of ordinary skill before the effective filing date of the invention would have recognized that the two CCR8 polypeptide sequences are functionally comparable, and thereby would have been able to substitute the polypeptide sequences with predictable results. Furthermore, the ordinary artisan also would have been motivated to utilize the γδ T-cells engineered to express CCR8 in the treatment of breast cancer, as breast cancer tumors highly express CCL1, which specifically binds to CCR8 (Kuehnemuth et al: Abstract; Pages 2-4). Therefore, one of ordinary skill would have recognized that the γδ T-cells engineered to express CCR8 as detailed in Jakobovits et al would have been beneficial in the treatment of breast cancer, as it would provide a targeted therapeutic given the CCL1/CCR8 interaction between the CCL1-expressing breast cancer tumors and the CCR8-expressing γδ T-cells, and would have had a reasonable expectation of success given the disclosure of Jakobovits et al. See MPEP § 2143(I)(G).
Consequently, Jakobovits et al as modified by Liang et al and Kuehnemuth et al render obvious a method of treating breast cancer within a subject, wherein primary γδ T-cells (claims 36-37) engineered to express a CCR8 polypeptide provided in GenBank™ accession number NP 005192.1 are administered to the subject in need thereof. It is of note that this CCR8 accession number has 100% sequence identity to instant SEQ ID NO: 1 (claim 35; see sequence alignment below). As breast cancer tumors express CCL1 within the tumor parenchyma, this therefore reads on the method of instant claim 33.
Query Match 100.0%; Length 355; Matches 355; Gaps 0
Qy 1 MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNGKLLLAVFYCLLFVFSLLGNSLVILVL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNGKLLLAVFYCLLFVFSLLGNSLVILVL 60
Qy 61 VVCKKLRSITDVYLLNLALSDLLFVFSFPFQTYYLLDQWVFGTVMCKVVSGFYYIGFYSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VVCKKLRSITDVYLLNLALSDLLFVFSFPFQTYYLLDQWVFGTVMCKVVSGFYYIGFYSS 120
Qy 121 MFFITLMSVDRYLAVVHAVYALKVRTIRMGTTLCLAVWLTAIMATIPLLVFYQVASEDGV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 MFFITLMSVDRYLAVVHAVYALKVRTIRMGTTLCLAVWLTAIMATIPLLVFYQVASEDGV 180
Qy 181 LQCYSFYNQQTLKWKIFTNFKMNILGLLIPFTIFMFCYIKILHQLKRCQNHNKTKAIRLV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LQCYSFYNQQTLKWKIFTNFKMNILGLLIPFTIFMFCYIKILHQLKRCQNHNKTKAIRLV 240
Qy 241 LIVVIASLLFWVPFNVVLFLTSLHSMHILDGCSISQQLTYATHVTEIISFTHCCVNPVIY 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LIVVIASLLFWVPFNVVLFLTSLHSMHILDGCSISQQLTYATHVTEIISFTHCCVNPVIY 300
Qy 301 AFVGEKFKKHLSEIFQKSCSQIFNYLGRQMPRESCEKSSSCQQHSSRSSSVDYIL 355 (SEQ ID NO: 1)
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 AFVGEKFKKHLSEIFQKSCSQIFNYLGRQMPRESCEKSSSCQQHSSRSSSVDYIL 355 (NP 005192.1)
Regarding claim 34: Following the discussion of claim 33, Jakobovits et al further disclose that the primary γδ T-cells are allogeneic to the subject (Paragraphs [0003], [0029], [0034], [0041], [0047], [0054]-[0060], [0113], [0129]). This therefore reads on the method of the instant claim.
Regarding claim 38: Following the discussion of claim 33, Jakobovits et al further disclose that the primary γδ T-cells are universal – or non-alloreactive (Paragraphs [0029]-[0031], [0042], [0059]-[0060], [0065], [0113]). As “universal” and “non-alloreactive” are synonymous – see instant Specification, Page 8 – this therefore reads on the method of the instant claim.
Regarding claim 39: As aforementioned in the discussion of claim 38, Jakobovits et al disclose universal primary γδ T-cells. As the γδ T-cells inherently do not express the TCR alpha or beta chain genes (Jakobovits et al: Paragraphs [0001], [0028]), this therefore reads on the method of the instant claim.
Regarding claim 40: Following the discussion of claim 39, Jakobovits et al further disclose that the primary γδ T-cells are further engineered to express a chimeric antigen receptor (Paragraphs [0004], [0029], [0033], [0052]-[0053], [0070]-[0071]). This therefore reads on the method of the instant claim.
Claims 33-41 are rejected under 35 U.S.C. 103 as being unpatentable over Jakobovits et al (US 2016/0175358 A1, of record on IDS filed 01 September 2021) in view of Liang et al (WO 2016/025454 A2, of record) and Kuehnemuth et al (BMC Cancer, 2018), and further in view of Frost et al (WO 2020/047527 A2, of record).
The discussion of Jakobovits et al as modified by Liang et al and Kuehnemuth et al regarding claims 33 and 38-40 can be observed above and is relied upon herein, the content of which is incorporated in its entirety. Jakobovits et al as modified by Liang et al and Kuehnemuth et al render obvious claims 33-40. Frost et al is considered prior art under 35 USC 102(a)(2), with a priority date of 02 September 2018.
Regarding claim 41: Following the discussion of claim 40, Jakobovits et al further disclose that the γδ T-cells are engineered to express a cytokine receptor (Paragraph [0056]).
The combination of Jakobovits et al, Liang et al, and Kuehnemuth et al fail teach that the universal primary γδ T-cells are further engineered to express a modified cytokine receptor that is dominant-negative TGF-β receptor 2, as required by instant claim 41.
Frost et al, however, disclose methods for genetically modifying T lymphocytes obtained from the blood of human subjects suffering from cancer, wherein the genetic modification involves inserting a polynucleotide encoding a CAR and a cytokine receptor lymphoproliferative element into the T lymphocytes. Frost et al further disclose that the cytokine receptor lymphoproliferative element is TGFβ decoy receptor, or dominant-negative TGF-β receptor 2 (Abstract; Paragraphs [0096]-[0097], [0118]-[0119], [0128], [0132], [0194]-[0199], [0294]-[0295]).
Frost et al further disclose that the T lymphocytes are γδ T lymphocytes (Paragraph [0038]).
Therefore, it would have been prima facie obvious to further modify the method of Jakobovits et al in view of Liang et al and Kuehnemuth et al such that the CCR8-expressing engineered γδ T-cells comprising CARs are further modified to comprise a dominant-negative TGF-β receptor 2 lymphoproliferative element, as detailed in Frost et al. One of ordinary skill before the effective filing date of the invention would have been motivated to utilize genetically engineered primary T lymphocytes that remove the need to proliferate the γδ T-cells in vitro prior to administering them to lymphodepleted subjects, such as those receiving adoptive T cell therapy, and would have had a reasonable expectation of success based on the disclosure of Frost et al (Paragraphs [0242]-[0244]). See MPEP § 2143(I)(G).
Consequently, Jakobovits et al as modified by Liang et al, Kuehnemuth et al, and Frost et al render obvious a method of treating breast cancer, wherein the CCR8-expressing engineered primary γδ T-cells comprising CARs are further modified to comprise a modified cytokine receptor that is dominant-negative TGF-β receptor 2. This therefore renders obvious the method of the instant claim.
Conclusion
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633