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
The instant application, 18/255,808 filed on 06/02/2023, is a 371 of PCT/CN2021/135151 filed on 12/02/2021 and claims priority to CN202011482080.0 filed on 12/15/2020 and CN202011399860.9 filed on 12/02/2020. The instant application will be examined with an effective priority date of 12/02/2020.
Status of the Application/Claims
Amended claim set submitted on 06/02/2023 is currently pending and is herein under examination on the merits. Claims 1 and 6-7 are amended.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/02/2023 is acknowledged and is in compliances with the provisions of CFR 1.97. It has been considered by the examiner.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because the claims are drawn to the “use of a CAR-immune cell targeting an NKG2D ligand in preparation of a medicament for:” claim 1 ln 1-2, which is a process and claims 2-9 do not further recite any active steps for use. The claims as recited no not recite any active steps involved in the process for preparing the medicament and therefore the claims are not a proper process, machine, manufacture or composition claim.
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.
Claims 1-8 are 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.
Regarding claim 1, it is rejected as being incomplete for active steps for the use claim rendering the claim indefinite because a skilled artisan would not be able to follow use the CAR-immune cell targeting an NKG2D ligand since the claim is missing the active steps for use.
Regarding claims 2-8, which are dependent on claim 1the claims do not further recite any active steps.
Regarding claim 1 and dependent claims 2-8, recite the phrase "preferably … and more preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
Claims 1-12 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0369285 A1, and further in view of Ovadya et al. “Strategies targeting cellular senescence.” The Journal of clinical investigation 128 4 (2018): 1247-1254 and Sagiv. et al. NKG2D ligands mediate immunosurveillance of senescent cells. Aging (Albany NY). 2016 Feb;8(2):328-44, here in further referred to as Dai, Ovadya and Sagiv respectively.
Regarding claim 1, Dai teaches a of a chimeric antigen receptor (CAR) and its modified immune response cells targeting NKG2D ligand that can be used to prepare preparations for the treatment of tumors (Dai Abstract). Dai further teaches that the modified immune response cells comprises a CAR targeting NKG2D ligand (Dai para. 0044), wherein the CAR comprises a polypeptide with an amino acid sequence SEQ ID NO: 9 (KD-025) which is capable of binding to several NKG2D ligands such as MICA, MICB, ULPB2, ULPB2 and ULPB3 (Dai para. 0010-0011, 0068 and Fig. 6B and Fig. 15).
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SEQ ID NO: 9 (Dai) with 100% local similarity to claimed SEQ ID NO: 1).
Dai does not specifically teach that the CAR-immune cell targeting NKG2D ligand can be used in the preparation of a medicament for eliminating senescent cells, where NKG2D is upregulated by 2-20, 4-15 or 10-20 times more in senescent cells than in normal cells, or for delaying individual aging and/or for preventing and or treating age-related diseases.
Ovadya teaches that NKG2D ligands are upregulated in senescent cell and also about different strategies for targeting cellular senescence including using immune-mediated interventions wherein CAR T cells can be used to target NKG2D ligands that are upregulated in senescent cells (Ovadya pg. 1250 col. 1 para. 3 – col. 2 para. 1-2).
Sagiv teaches NKG2D ligands such as MICA and ULBP2 are consistently upregulated following induction of replicative senescence, oncogene-induced senescence and DNA-damage induced senescence and that in liver fibrosis, the accumulation of senescence activated stellate cells is increased in mice lacking NKG2D receptor leading to increase fibrosis (Sagiv Abstract). Sagiv also teaches of upregulation of several NKG2D ligands in different types of senescent cells as compared to normal fibroblast cells where in the expression of ULBP4 is about 10 times more in HSC DIS cell lines than in normal fibroblast cell line (Sagiv Fig. 1). Sagiv also teaches that to eliminate senescent cells NK cells utilizes NK cells and that NK cell mediated immune surveillance is necessary for the immunosurveillance of senescent cells during tumorigenesis, tumor therapy and tissue damage (Sagiv pg. 329 col. 1 para. 3).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Dai in view of Ovadya and Sagiv with a reasonable high degree of predictable success to use Dai’s NKG2D-CAR immune cells comprising the claimed amino acid sequence that targets NKG2D ligands in a medicament where in the NKG2D-CAR immune cells will target NKG2D ligands such as such as MICA, MICB, ULBP2, ULBP3 (as indicated by Sagiv, Fig. 1) that are upregulated or overexpressed by senescent cells. A skilled artisan would have been able to design such a medicament for eliminating NKG2D ligands that are known to cause toxicity when upregulated in senescent cells thereby causing age related diseases, and therefore, a skilled artisan would have been motivated to modify the methods of Dai in view of Ovadya and Sagiv to prepare a medicament comprising the NKG2D-CAR immune cell targeting NKG2D ligands so as to eliminate senescent cells causing age-related diseases thereby preventing or treating the disease.
Regarding claim 2, and incorporating the analysis of claim 1 above, Dai further teaches that the CAR comprises a guided sequence, an extracellular domain targeting human NKG2D ligand, a transmembrane domain, and intracellular signaling domain connected sequentially (Dai para. 0012), where in the CAR comprises a guiding sequence (the signal peptide sequence) , a human NKG2D sequence according to claim 1 , a human CD8 hinge region sequence , a human CD8 transmembrane region sequence, a human CD28 intracellular domain sequence, a human 4-1BB intracellular domain sequence, and a CD3 zeta intracellular domain sequence which are sequentially connected (Dai para. 0027).
Regarding claim 3, and incorporating the analysis of claim 1 above, Dai further teaches that EF1 alpha promoter can be used to promote the expression of the CAR (Dai para. 0040-0042).
Regarding claim 4 and 5, and incorporating the analysis of claim 1 above, Sagiv further teaches that the senescent cells that express upregulation of NKG2D ligands included human diploid fibroblast and human hepatic myofibroblast induced senescent cells (Sagiv pg. 340 col. 2 para. 2).
Regarding claim 6 and 7, and incorporating the analysis of claim 1 above, Sagiv teaches that HSC cells become senescent during liver fibrosis (Sagiv pg. 330 col. 2 para 1) and can lead to increased liver fibrosis (Sagiv pg. 329 col. 2 para. 1).
Therefore, it would have been obvious for a skilled artisan to modify the teachings of Dai in view of Ovadya and Sagiv with a reasonable high degree of predictable success to use the NKG2D-CAR immune cells of Dai to prepare a medicament that will prevent and/or treat by eliminating the senescent cells causing an increased in liver fibrosis during liver damage as indicated by Sagiv.
Regarding claim 8, and incorporating the analysis of claim 1 above, Sagiv further teaches of mice infected with senescent activate hepatic stellate cells that expressed NKG2D ligands about 2 to ten time more than in normal cells (Sagiv Abstract and Fig. 1).
Claims 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Dai and further in view of Ovadya, Sagiv, Kim et al. Senotherapeutics: emerging strategy for healthy aging and age-related disease. BMB Rep. 2019 Jan;52(1):47-55, Zhu et al. (2015), The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell, 14: 644-658 and Pereira et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat Commun 10, 2387 (2019), herein further referred to as Kim, Zhu and Pereira.
Regarding claims 9 and 10, Dai teaches of a pharmaceutical composition comprising a CAR-immune cell targeting NKG2D ligand wherein the CAR comprises an antigen binding domain comprising a polypeptide with an amino acid sequence SEQ ID NO: 9 and capable of binding NKG2D ligands (Dai para. 0010-0012) and the composition further comprising a pharmaceutically acceptable excipient (Dai para. 0049).
Dai does not teach that composition comprises another anti-aging drug other.
Kim teaches that the use of senolytic agents is an emerging strategy for healthy aging and treatment of age-related diseases, and that a combination of dasatinib plus quercetin that targets the Pan-receptor tyrosine kinase and other pathways have been used in a study to increase lifespan in animal models and for treating other age-related conditions (Kim Abstract and Tab 1). Kim further teaches that T cells engineered to express the NKG2D-CAR that recognizes NKG2D ligands such as MICA and ULBP2 (ligands expressed on the surfaces of senescence cells) may be a used to target accumulated senescence cells for elimination (Kim pg. 52 col. 1 para 4 – col 2 para 1 and Tab. 3).
Zhu teaches that dasatinib plus quercetin have better senolytic activity against certain types of senescent cell than others and therefore a strategy where additional senolytics that targets a specific type of senescent cells can be used in combination with dasatinib plus quercetin can be employed (Zhu pg. 651 col. 1 para. 2-3 and col. 2 para. 1).
Pereira teaches that despite the development of senolytic drugs that target senescent cells has shown to successfully reversing age-related pathologies in animal models, but the use of senolytic drugs in humans may be hampered by their lack of specificity for senescent cells which may lead to off-target toxicity and therefore, alternative approaches can be used in isolation or in combination with senolytic drugs to improve the elimination of senescent cells in human can be exploited (Pereira pg. 2 col. 1 para. 1). Pereira also teaches that senescent cells express MICA/B that bind to NKG2D and activate their killing by the NK cells and that senescent cells secrete chemokines and cytokines that enables the recruitment of immune cells into tissues that enable the clearance of senescent cells (Pereira pg. 2 col. 1 para. 2).Therefore, it would have would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Dai in view of Ovadya, Sagiv, Kim, Zhu and Pereira with a reasonable high degree of predictable success where in the composition comprising the NKG2D-CAR immune cells as claimed and dasatinib plus quercetin will eliminated senescent cells thereby increasing lifespan. As indicated by Zhu and Pereira, senolytics lack specificity to senescent cells and may cause toxicity at high doses and that combining senolytics with other strategies for eliminating senescent cells with more specificity by using immune-system mediated such as composition of Dai is a strategy to explore, wherein the NKG2D-CAR immune cells with specificity to NKG2D ligands such as MICA, ULBP2, wherein the binding of the NKG2D-CAR immune cell to the NKG2D ligands (MICA, ULBP2) will eliminate the senescent cells. Furthermore, Kim indicates that senolytic drugs such as dasatinib plus quercetin eliminate senescent cells through a pathway mechanism, while NKG2D-CAR targets MICA, ULBP2 and other NKG2D ligands that are overexpressed in senescent cells. Therefore, a skilled artisan would have been motivated to use a strategy as suggested by Pereira and Zhu to design a composition that combines a senolytic drug such as dasatinib plus quercetin as indicated by Kim and Zhu with an NKG2D-CAR immune cell as indicated by Dai, wherein dasatinib plus quercetin is administered at a reduced dose so as to minimize off-target effects caused by the senolytic drug that targets a common pathways (such as Pan-receptor tyrosine kinase) and the NKG2D-CAR immune cells targets the senescent cells that expresses MICA, ULBP2 or other NKG2D ligands with better specificity to senescent cells.
Regarding claim 11, and incorporating the analysis of claim 9 above, Dai further teaches that the composition can be in the form and an injection (Dai para. 0213).
Regarding claim 12, and incorporating the analysis of claim 9 above, Dai further teaches of a safety tolerance dose and toxicology test results when KD-025 CAR was administered to B-NSG animals (Dai para 0073) wherein the doses ranges from 5 x 105 to 5 x 107 cells/kg.
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Dai in view of Ovadya, Sagiv, Kim, Zhu and Pereira with a reasonable high degree of predictable success to us the method of Dai, in order to determine the dose of the NKG2D-CAR immune cells required for the pharmaceutical composition that will elucidate a tolerable toxicity.
Claims 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over US20200131244A1 and further in view of Dai, and as evidenced by UniProt Retrieved from <www.uniprot.org/uniprotkb/P26718/feature-viewer> on 04/15/2026, herein further referred to as Leong and UniProt respectively
Regarding claims 13-15, Leong teaches a CAR-immune cell expressing a chimeric antigen receptor (Leong Abstract) having structure as indicated in the figure below (Leong Fig. 15) having the sequence as shown below (SEQ ID NO: 19) having 97.7% similarity to the claimed SEQ ID NO: 12 of claim 14, wherein an NKG2D fragment is used, CD8α is a transmembrane domain which can further comprise a CD8α hinge region, a CD3zeta intracellular signaling domain further comprising a 4-1BB signaling domain (Leong para. 0007-0008)
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SEQ ID NO: 19 of Leong
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Leong further teaches that subunits of NKG2D can be replaced with one or more additional subunits so as to improve cytotoxicity or activation of NK cells (para 0102, 0137). US’244 also teaches that the CAR comprising SEQ ID NO: 19 having a truncation at 73-81 had a synergistic effect with respect to activation and cytotoxicity nature of the NK cells (para. 0155).
Dai teaches a CAR comprising full extracellular domain amino acid sequence SEQ ID NO: 19 comprising amino acid residues 73-216 of NKG2D.
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Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Leong in view of Dai with a reasonable high degree of predictable success to use the amino acid sequence SEQ ID NO: 1 for the design of the CAR comprising SEQ ID NO: 12 wherein the SEQ ID NO: 19 of Leong only differs in the claimed SEQ ID NO: 12 in that the extracellular domain of Leong’s construct comprises the amino acids 82-216 of the full length NKG2D extracellular domain while the instant application comprises amino acids 73-216, the full extracellular domain (ECD) (UniProt).
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UniProt (ECD of NKG2D)
Furthermore, it is also common in the art to use the full ECD for the design of CAR as exemplified by Dai, of a truncated NKG2D as indicated by Leong to achieve desired cytotoxic or activation outcomes. Therefore a skilled artisan would have been able to modify the CAR of Leong wherein the NKG2D ECD used comprises amino acids 82-216 to use the NKG2D of Dai comprises amino acids 73-216 which is commonly used for CAR designs and to achieve desired therapeutic outcomes.
Conclusion
No claims allowed.
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/EMMANUEL LED YOUTCHOM PENDIE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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