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 .
This action is in response to the papers filed on 06/12/2026. Claims 1-23 are currently pending as per claims filed on 06/12/2026. Applicant’s election of Group I, claims 1-10, 16, and 17, without traverse, in the reply filed on 06/12/2026 is acknowledged.
Therefore, claims 11-15 and 18-23 are withdrawn by Applicants from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected group, there being no allowable generic or linking claim.
The requirement is still deemed proper and is therefore made FINAL.
Therefore, claims 1-10, 16, and 17 are subject to examination to which the following grounds of rejection are applicable. Claims 1 and 16 are independent claims.
Priority
The instant application claims benefit to US Provisional application no. 63/482,264 filed 01/30/2023.
Thus, the earliest possible priority for the instant application is 01/30/2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/01/2024, 08/02/2024, and 03/26/2025 was filed before the mailing date of the current office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 1 is objected to because abbreviations such as PD-L1 and HGF should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim 6 is objected to because abbreviations such as ELISA should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim 7 is objected to because abbreviations such as CXCR4 should be spelled out at the first encounter in the claims. Appropriate correction is required.
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 2, 4-8 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.
Claim 2 recites “exogenous PD-L1 gene comprises the amino acid sequence of SEQ ID NO: 4” and “exogenous HGF gene comprises the amino acid sequence of SEQ ID NO: 5”. Genes do not comprise amino acids, but rather comprise nucleotides. Applicant should amend to recite the correct terminology.
Claim 4 recites the phrase “an overexpression PD-L1 and an overexpression HGF”. The specification defines “overexpression” as a significant increase in the expression level relative to a normal condition (para 0074). However, it is unclear which ones are the comparative normal conditions for overexpression of the exogenous PD-L1 and exogenous HGF genes.
Claims 5 and 6 inherit these deficiencies as they depend on claim 4.
Claim 7 recites the phrase “an overexpression CXCR4”. The specification defines “overexpression” as a significant increase in the expression level relative to a normal condition (para 0074). However, it is unclear which ones are the comparative normal conditions.
Claim 8 inherit these deficiencies as they depend on claim 7.
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.
Claim(s) 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (CN112921003 A; as cited in IDS) and further in view of Shyu et al (WO 2021057942 A1), UniProt HGF (P14210 – HGF HUMAN, first entered 08/01/1991, downloaded 06/24/2026), UniProt PD1-L1 (Q9NZQ7 - PD1L1 HUMAN, first entered 10/01/2000, downloaded 06/24/2026), Liu et al (Scientific Reports, 2017, pages 1-9), and Hong et al (US 20180369410 A1).
The applied Shyu reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). The publication dated for Shyu is 01 April 2021. The earliest effective filing date of the instant application is 20 January 2023.
Therefore rejection under 35 U.S.C. 103 CANNOT be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)© establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02. Because the reference qualifies as prior art under 102(a)(1), the provisions of MPEP 717.02 do not apply.
Regarding claim 1, Wang teaches a mesenchymal stem cell (MSC)-derived exosome expressing a PD-L1 molecule wherein the MSC-derived exosome is generated by transfecting the MSCs with lentiviruses carrying PD-L1 plasmids (page 3, para 6, step 2) (i.e. genetically engineered MSCs comprising an exogenous PD-L1 gene). Wang teaches “the PD-1/PD-L1 pathway plays an important role in inhibiting the initial and effector stages of immune response and maintaining the immune homeostasis of the body.” and “The ability to negatively modulate the immune response using the PD-1/PD-L1 pathway is of potential clinical interest in the treatment of immunoinflammatory disorders.” (page 2, para 4)
Wang does not teach wherein the genetically modified mesenchymal stem cell comprises an exogenous HGF gene.
However, one of ordinary skill in the art would have considered the teachings of Shyu as this reference is analogous prior art pertaining to genetically engineering mesenchymal stem cells with exogenous HGF and PD-L1 genes for therapeutic purposes.
Shyu teaches genetically engineered mesenchymal stem cells (MSCs) comprising an expression vector comprising an HGF gene and a PD-LI gene (abstract page 1). Shyu teaches that the genetically engineered MSCs comprising an HGF gene and a PD-LI gene can be used to treat and ameliorate ischemia conditions, enhance neuroregeneration or reduce neuronal death (para 0005) and that when HGF and PD-L1 were combined in a vector system, the beneficial effects were greater than with either gene alone as evidenced in FIG 3A and 3B.
It would have been prima facie obvious to one of ordinary skill, in the art before the effective filing date of the claimed invention, to modify the teachings of MSC-derived exosomes expressing a PD-L1 molecule wherein the MSC-derived exosome is generated by transfecting the MSCs with PD-L1 plasmids from Wang with the teachings of MSCs comprising expression vectors comprising both an HGF and PD-L1 gene from Shyu to arrive at an exosome that is derived from a genetically modified MSC where in the MSC comprises plasmids/vectors comprising both the HGF gene and PD-L1 gene. One would be motivated to do so as Shyu teaches that MSCs comprising both exogenous HGF and PD-L1 genes can treat and ameliorate ischemia conditions, enhance neuroregeneration or reduce neuronal death relative to using solely a HGF gene or a PD-L1 gene. As generating exosomes from MSCs and transfecting exosomes with exogenous genes is known in the art, one would have a reasonable expectation of success.
Regarding claim 2, the teachings of Wang and Shyu render obvious claim 1.
The combined teachings of Wang and Shyu do not teach wherein the exogenous PD-L1 gene comprises the amino acid sequence of SEQ ID NO: 4, and the exogenous HGF gene comprises the amino acid sequence of SEQ ID NO: 5.
However, one of ordinary skill in the art would have considered the teachings of UniProt HGF and UniProt PD1-L1 as these references teach the known polypeptide sequences for Human HDG and Human PD1-L1, respectively, thus rendering obvious the exogenous PD-L 1 gene encoding SEQ ID NO:4 and the exogenous HGF gene encoding SEQ ID NO:5.
UniProt PD-L1 teaches a polypeptide sequence that is 100% identical to the sequence set forth in SEQ ID NO: 4. See alignment below:
PNG
media_image1.png
495
632
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Greyscale
Qy: SEQ ID NO: 4, Db: UniProt PD1-L1 polypeptide sequence
PNG
media_image2.png
760
675
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Greyscale
UniProt HGF teaches a polypeptide sequence that is 100% identical to the sequence set forth in SEQ ID NO: 5. See alignment below:
PNG
media_image3.png
418
640
media_image3.png
Greyscale
Regarding claim 3, the teachings of Wang and Shyu render obvious claim 1.
The combined teachings of Wang and Shyu do not teach wherein the exogenous PD-L1 gene and the exogenous HGF gene are linked by a self-cleaving peptide coding fragment.
However, one of ordinary skill in the art would have considered the teachings of Liu as this reference is analogous prior art pertaining to the use of self-cleaving peptides for multi-gene co-expression.
Liu teaches co-expression of multiple genes at a desired ratio is highly attractive for a broad array of basic research and biomedical applications including expression of multiple subunits of complex multimeric proteins in gene therapy (page 1, para 1). Liu teaches strategies for multigene co-expression include “self-cleaving” 2A peptides and the self-cleaving peptides lead to relatively high levels of downstream protein expression compared to other strategies for multi-gene co-expression, and they are small in size thus bearing a lower risk of interfering with the function of co-expressed genes. (page 1, para 1).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of genetically engineered MSCs comprising a vector comprising an HGF and PD-L1 gene such that the genetically engineered MSCs produce exosomes, as taught by Wang and Shyu, to link the HGF and PD-L1 genes by a self-cleaving peptide coding fragment as Liu teaches that, when generating multiple polypeptides from a single vector (i.e. multigene co-expression), its is preferable to link the genes through a self-cleaving peptide as the self-cleaving peptide leads to relatively high levels of downstream protein expression and they are small in size thus bearing a lower risk of interfering with the function of co-expressed genes. One would be motivated to do so to ensure proper translation of the linked HGF and PD-L1 genes that are linked on the same vector/fragment. As use of self-cleaving peptides and exogenous expression of vectors comprising HGF and PD-L1 have been shown in the art, one would have a reasonable expectation of success.
Regarding claim 4, the teachings of Wang and Shyu render obvious claim 1.
It is noted that the “wherein” clause of the exosome provides no patentable weight, as the characteristics are a direct result of the structure of the exosome of the independent claim 1, absent evidence to the contrary.
Regarding claim 5, the teachings of Wang and Shyu render obvious claim 1 and 4. It is noted that the “wherein” clause of the PD-L1 expression level of the exosome provides no patentable weight, as the characteristics are a direct result of the structure of the exosome of the independent claim 1, absent evidence to the contrary. Moreover, flow cytometry test to measure specific proteins on cells was routine and well known in the art before the effective filing date of the claimed invention.
Regarding claim 6, the teachings of Wang and Shyu render obvious claim 1 and 4. It is noted that the “wherein” clause of the HGF content of the exosome provides no patentable weight, as the characteristics are a direct result of the structure of the exosome of the independent claim 1, absent evidence to the contrary. Moreover, ELISA to detect and quantify specific antibodies, antigens or proteins in a sample was routine and well known in the art before the effective filing date of the claimed invention.
Regarding claim 7, the teachings of Wang and Shyu render obvious claim 1.
The combined teachings of Wang and Shyu do not teach wherein the exosome comprises an overexpression CXCR4 on an exosome membrane thereof.
However, one of ordinary skill in the art would have considered the teachings of Hong as this reference is analogous prior art pertaining to exosomes comprising CXCR4 on the membrane.
Hong teaches human MSC-derived exosomes that express markers from MSCs, such as CXCR4, on their membranes which enable homing properties (para 0037-0038, 0040, 0102). Hong teaches the expressed markers such as CXCR4 will mediate interactions with angiogenic, inflamed endothelia via a series of interactions involving rolling (P-selectin) and firm adhesion (VCAM-1 and SDF-1), respectively, resulting in efficient extravasation to reach the cancerous tissue (para 0037).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of genetically engineered MSCs comprising a vector comprising an HGF and PD-L1 gene such that the genetically engineered MSCs produce exosomes comprising HGF and PD-L1 genes, as taught by Wang and Shyu, to additionally include overexpression of CXCR4 on the membrane of MSC-derived exosomes, as taught by Hong, to achieve an exosome which comprises overexpression of PD-L1, HGF, and, on the membrane, CXCR4. One would be motivated to do so since Hong teaches that the expression of CXCR4 on the membrane mediates interactions with angiogenic, inflamed endothelia via a series of interactions and results in efficient extravasation to reach cancerous tissue. As expression of CXCR4 on exosomes has been shown in the prior art, one would have a reasonable expectation of success.
Regarding claim 8, the teachings of Wang and Shyu render obvious claim 1 and 7. Moreover, flow cytometry test to measure specific proteins on cells was routine and well known in the art before the effective filing date of the claimed invention. Thus, the proportion of exosome increase with CXCR4 surface would have been obvious in view of the teachings of Hong where expression of CXCR4 results in efficient extravasation to reach cancerous tissue.
Regarding claim 9 and 10, the teachings of Wang and Shyu render obvious claim 1. Moreover, Wang teaches the particle size of the exosome is 80-120 nm (page 2, last paragraph), falling within the range of 30-200 nm and 100-150 nm recited in claim 9 and 10, respectively.
Claim(s) 1, 16, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Wang and Shyu as applied to claim 1 above, and further in view of Mitsialis et al (WO 2015179227 A1).
References Wang and Shyu teach the exosomes of claim 1 as discussed above, the contents of which is incorporated herein in it's entirety.
Regarding claim 16 and 17, the combined teachings of Wang and Shyu do not teach a pharmaceutical composition for treating an ischemia condition of a tissue, comprising: the exosome of claim 1; and a pharmaceutically acceptable carrier (claim 16) and wherein an administration route of the pharmaceutical composition is intravenous injection, intracarotid artery injection, intraarterial injection or a combination thereof (claim 17).
However, one of ordinary skill in the art would have considered the teachings of Mitsialis as this reference is analogous prior art pertaining to MSC-derived exosomes for treating ischemic disease and their inclusion in a pharmaceutical composition.
Mitsialis teaches exosomes isolated from mesenchymal stem cells (MSC) wherein in the exosomes may be used in pharmaceutically acceptable preparations/compositions when combined with a pharmaceutically acceptable carrier and can be intravenously injected (page 2, line 10; page 30 line 6-10). Mitsialis teaches that the a pharmaceutically acceptable carrier is involved in carrying or transporting a prophylactically or therapeutically active agent such as the exosome (page 28, line 23-30).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to combine the teachings of exosomes derived from genetically engineered MSCs comprising exogenous PD-L1 and HGF gene, as taught by Wang and Shyu, with the teachings of a pharmaceutical composition comprising MSC-derived exosomes and a pharmaceutically acceptable carrier from Mitsialis to arrive at a pharmaceutical composition comprising: MSC-derived exosomes comprising exogenous PD-L1 and HGF genes and a pharmaceutically acceptable carrier. One would be motivated to do so as Mitsialis teaches that the pharmaceutical composition comprising the pharmaceutically acceptable carrier permits the transport of the exosome when administered in vivo via intravenous injection. As generating pharmaceutical compositions comprising pharmaceutical acceptable carriers and exosomes is known in the art, one would have a reasonable expectation of success.
Conclusion
No claims are allowed.
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/JULIANA IRENE CANDELARIA/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634
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