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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/16/2025 has been entered.
Status of the Claims
Claims 1 – 7 and 10 – 20 were pending. Claims 1, 3, 14 – 16, and 18 have been amended, and claims 2, 5 – 6, 12 – 13, and 17 have been canceled. Claims 1, 3 – 5, 10 – 11, 14 – 16, 18, and 19 – 20 are currently pending, with non-elected claims 10 – 11 and 19 – 20 are withdrawn from consideration. Claims 1, 3 – 5, 14 – 16, and 18 are examined on the merits and are the subject of this Office Action.
Claim Objections
Claim 18 is objected to because of the following informalities: on lines 1-2 the claim should recite the article “the” between “wherein” and “plasmid”. 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.
Previous rejection, withdrawn: claims 14, 15, and 17 and 18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to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.
In view of the claim amendments in the reply of 10/16/2025, this rejection is withdrawn.
New rejection, necessitated by claim amendments: claims 14 – 15 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 14 recites the limitation “wherein cell.” Claim 14 depends from claim 1. There is insufficient antecedent basis for this limitation in the claim from which it depends.
Claim 15 recites the limitation “the process further comprises nanotransfecting the cell” Claim 15 depends from claim 1. There is insufficient antecedent basis for this limitation in the claim from which it depends.
Claim Interpretation
According to the present specification, “EVs can in some embodiments be any vesicle that can be secreted by a cell. Cells secrete extracellular vesicles (EVs) with a broad range of diameters and functions, including apoptotic bodies (1-5 μm), microvesicles (100-1000 nm in size), and vesicles of endosomal origin, known as exosomes (50-150 nm)” (paragraph 0041 of the pre-grant publication).
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.
Previous rejection, maintained in modified form: claims 1, 14, and 15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e. a natural product) without significantly more.
Claim 1 recites an extracellular vesicle (EV) with an ICAM1 that comprises at least 100 contiguous amino acids of SEQ ID NO: 1 capable of binding the amino acid of SEQ ID NO: 2. This judicial exception is not integrated into a practical application because the claim recites a naturally occurring EV with a naturally occurring ICAM, which comprises the claimed SEQ ID NO: 1. The claim(s) does not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Claim 1 is evaluated using the “Subject Matter Eligibility Test for Products and Processes” flow chart as shown in MPEP § 2106 (III).Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Yes. The claim is drawn to a composition of matter (product) which is one of the four statutory categories.Step 2A, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes. The claims are directed towards natural phenomenon (product of nature) of an EV with an ICAM1 that comprises at least 100 contiguous amino acids of SEQ ID NO: 1 capable of binding the amino acid of SEQ ID NO: 2. According to the present specification, an EV may be an exosome (see claim interpretation above), according to SEGURA (a reference of record and rejections below and a reference submitted on the IDS of 08/15/2022), “exosomes are enriched in MHC class II, B7.2, intercellular adhesion molecule 1 (ICAM-1)” (see abstract). In the broadest reasonable interpretation of the claim, the EV, as claimed, comprises ICAM1 comprising SEQ ID NO: 1 which is 100% identical to mouse ICAM (see Appendix), as evidenced by “Nucleotide sequence of the cDNA for murine intercellular adhesion molecule-1 (ICAM-1)”, Ballantyne et al, published November 4, 1989 (see PTO-892 submitted with this Office Action).
Murine ICAM1 is naturally present on exosomes (extracellular vesicles) secreted by dendritic cells in mice. In addition, naturally occurring dendritic cells comprise nucleic acid encoding murine ICAM1 in order to produce the exosomes. As evidenced by SEGURA, murine immature dendritic cells naturally secrete exosomes (Abstract, Intro). SEGURA teaches that proteomic and biochemical analyses revealed that mature exosomes are enriched in ICAM-1 compared to immature dendritic cells, but present in both (Figure 5). SEGURA teaches the exosomes produced by murine DCs comprise ICAM1 (Figure 5). Additionally, SAKURADA (Shinsaku Sakurada, Tetsuji Kato, Takashi Okamoto, International Immunology, Volume 8, Issue 10, October 1996, Pages 1483–1493, https://doi.org/10.1093/intimm/8.10.1483; See PTO-892 submitted with this Office Action) teaches that fibroblasts express ICAM-1. See abstract and Fig. 6 .
Further, LU (Lu, Y.-Y., Wu, C.-H., Hong, C.-H., Chang, K.-L., & Lee, C.-H. (2021). Life, 11(6), 505. https://doi.org/10.3390/life11060505 teaches that Glut1 is expressed in fibroblasts; See PTO-892 submitted with this Office Action). See Abstract and Figs. 2 and 3 Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
No. Although the claims have been amended to include method steps, the present claims recite a product by process. Products-by-process claims are not limited to the manipulations of the recited steps, only the structure that is implied by the steps. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. See MPEP 2113.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No. The judicial exception is recited without additional limitations amounting to significantly more than the exception. While instant claim 1 recites An EV comprising ICAM1, all claimed limitations are considered to be the recitation of a natural phenomenon (e.g., naturally occurring protein and binding characteristics) and, therefore, do not amount to significantly more than the judicial exception that is claimed.
Claim Rejections - 35 USC § 102
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 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.
Previous rejection, withdrawn: claim 1 was rejected under 35 U.S.C. 102(a)(1) as being anticipated by KLIMUK (WO1997046671A1, Klimuk et al, published December 1997; see PTO-892: Notice of References Cited of 05/06/2025), as evidenced by UNIPROT (UniProt P13597, ICAM1_Mouse (printed April 2025); see PTO-892 of 05/06/2025) .
In view of the claim amendments of 10/16/2025, this rejection is withdrawn.
Previous rejection, maintained in modified form: claims 1 and 14 are rejected under 35 U.S.C. 102(a)( (1) as being anticipated by SEQURA (“ICAM-1 on exosomes from mature dendritic cells is critical for efficient naïve T-cell priming,” Segura et al, published July 1, 2005; an IDS reference submitted 08/15/2022; see PTO-892 of 05/06/2025).
SEGURA teaches that murine dendritic cells naturally secrete exosomes. SEGURA also teaches that proteomic and biochemical analyses revealed that mature exosomes are enriched in ICAM-1 compared to immature dendritic cells (Abstract). SEGURA also teaches that ICAM-1 is necessary for the immune activity of exosomes secreted by LPS-treated DCs.
In order to study exosomes produced by dendritic cells, SEGURA cultured dendritic cells, then purified exosomes produced by the cells purified from the supernatant of cultured cells (page 217, left column), followed by in vitro T-cell stimulation and finally injection of the exosomes or DCs into the hindfootpad of mice (page 217).
SEGURA teaches exosomes produced by murine DCs, a composition of immature and mature exosomes based on LPS treatment (page 220). SEGURA teaches the exosomes produced by murine DCs comprise ICAM1 (Figure 5). SEGURA also teaches the importance of ICAM-1 for increased immunogenicity in mature exosomes and teaches that exosomes purified from exosomes from wildtype murine dendritic cells express ICAM1 (Figure 7).
SEGURA does not specifically teach that the ICAM1 comprises SEQ ID NO:1. Given SEGURA teaches the ICAM1 exosomes are produced in mice by murine DCs, it is reasonably expected that the murine DCs inherently encode the murine ICAM1 sequence of instant SEQ ID NO:1 that is murine ICAM1. The claimed exosomes (extracellular vesicles) and cell appears to be the same as the prior art exosomes and cell, absent a showing of unobvious differences. The Office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Claim 1 further recites method steps of producing the extracellular vesicle and claim 14 recites that the cell is not a dendritic cell, however, the process by which the EV was made does not distinguish the claimed protein sequence from the prior art protein sequence. MPEP 2113 states: The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable, even though the prior product was made by a different process.
Response to Arguments
On p. 4, last paragraph – p. 5, second paragraph, Applicant argues that “[a]s noted in MPEP 2173.05(f), a product-by-process claim, which is a product claim that defines the claimed product in terms of the process by which it is made, is proper. In re Luck, 476 F.2d 650, 177 USPQ 523 (CCPA 1973); In re Pilkington, 411 F.2d 1345, 162 USPQ 145 (CCPA 1969); In re Steppan, 394 F.2d 1013, 156 USPQ 143 (CCPA 1967).
As further noted in MPEP 2113, ‘The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979).’ In other words, the product claimed by its method of production is novel if the process steps imply a structure that is distinct from the prior art.
One of ordinary skill in the art would certainly understand that an EV produced from a
fibroblast is very different from one produced from a DC - even if the fibroblasts are engineered to display ICAM1. For at least this reason, Applicant respectfully requests the withdrawal of this rejection.”
Applicant’s argument is not persuasive because the claimed EV has a structure that is indistinguishable from an EV found in nature or described in the prior art as discussed in the 102 rejection above. MPEP 2113 states that even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. In this case, the product, as claimed, may be an exosome with an ICAM that is found in nature, as evidenced by the prior art discussed above. No additional features distinguish the structure of the claimed EV from that described in the prior art.
Regarding Applicant’s reference to MPEP 2173.05(f), this section of the MPEP states that “[a] claim which makes reference to a preceding claim to define a limitation is an acceptable claim construction which should not necessarily be rejected as improper or confusing under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.” Present claim 1, which is rejected under 102 above, is an independent claim directed to a product. Thus, the argument referencing MPEP 2173.05(f) does not apply within the context of 102 rejection and/or the contents of claim 1.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous rejection, withdrawn: claims 1-3, 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over US20170182182A1, Seow et al, published June 29, 2017, in view of WO1997046671A1, Klimuk et al, published December 1997, as evidenced by UniProt P13597, ICAM1_Mouse (printed April 2025).
In view of the claim amendments in the reply of 10/16/2025, this rejection is withdrawn.
New rejection, necessitated by claim amendments: claims 1, 3, 14, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over SEOW (US20170182182A1, Seow et al; see PTO-892 of 05/06/2025) in view of KLIMUK and WIKLANDER (GB-2552774-A; see PTO-892 of 05/06/2025).
SEOW teaches modifying exosomes for the delivery of genetic material, particularly in methods of gene therapy (Abstract, [0004][0008]).
KLIMUK is directed to an extracellular vesicle (EV) comprising a binding protein, characterized in that at least one small molecule agent is bound to the binding protein. See claim 1. KLIMUK teaches the sequence of SEQ ID NO: 1 with 100% identity. See Appendix.
WIKLANDER is directed to extracellular vesicles (EVs) are disclosed comprising a binding protein which may be used for delivery of protein-drug conjugates. See abstract. WIKLANDER teaches methods of producing EVs that may be carried out using EVs obtained from any suitable EV-producing cell, for instance MSCs, fibroblasts, immune cells, HEK cells, and any other suitable cell type. See p. 18, third paragraph. Thus, WIKLANDER teaches that EVs can be obtained from fibroblasts and the EV protein is ICAM-1. See p. 10-3rd paragraph, p. 18-3rd paragraph and claim 7.
Regarding claim 1, SEOW teaches modifying an exosome to comprise a targeting moiety expressed on the surface of the exosome which binds to a moiety present on the cell to be targeted, wherein the targeting moiety is expressed as a fusion protein with an exosomal transmembrane protein (Ref. claim 8). SEOW teaches targeting of exosomes to a desired cell type is achieved by expressing a targeting moiety on the surface of the exosomes, and specifically teaches ICAM-1 as an example of an exosomal transmembrane protein to be used to modify the surface of exosomes [0048], (Claim 9).
SEOW does not teach the ICAM1 used to modify the surface of exosomes comprises SEQ ID NO: 1. KLIMUK remedies this deficiency.
KLIMUK teaches amino acid SEQ ID NO: 537 of mouse intercellular adhesion molecule-1. SEQ ID NO: 537 is 100% identical to instantly claimed SEQ ID NO: 1. See Appendix.
Given the ICAM protein taught by KLIMUK is 100% identical to instant SEQ ID NO:1, it necessarily comprises the instantly claimed function of binding to SEQ ID NO:2.
It would have been prima facie obvious to a person of ordinary skill in the art to make an extracellular vesicle comprising ICAM1 and further comprising therapeutic cargo, as taught by SEOW, using the known ICAM1 sequence taught by KLIMUK in fibroblasts, as taught by WIKLANDER.
One of ordinary skill in the art would have been motivated to and have a reasonable expectation of success given: 1) SEOW teaches modifying the surface of exosomes with a targeting moiety with ICAM1 for targeting to a specific cell type and therapeutic delivery, 2) SEOW teaches successfully loading the exosomes with miRNA for gene therapy, 3) KLIMUK teaches a known ICAM1 sequence that can be predictably and readily substituted for the ICAM1 of SEOW, and 4) WIKLANDER teaches a method of producing EVs in fibroblasts.
MPEP 2144.06 states that substituting functional equivalents is a rationale supporting obviousness. In the instant case, SEOW teaches modifying the surface of exosomes with ICAM1 protein, KLIMUK teaches a known ICAM1 protein sequence, and WIKLANDER teaches a method of producing the exosomes in fibroblasts. One of skill in the art would predictably and successfully utilize the known ICAM1 sequence of KLIMUK for the ICAM1 protein modifying the surface of the exosomes of SEOW in WIKLANDER’s method of producing EVs with a reasonable expectation of success.
Regarding claim 3, SEOW teaches loading exosomes with exogenous genetic material for delivery for use in gene therapy and gene silencing. SEOW teaches suitable genetic material for delivery includes exogenous DNA plasmid, siRNA, modified oligonucleotides, and other RNA interference effector moieties, such as miRNA and shRNA [0009][0030][0038]. SEOW teaches a method of loading exosomes with genetic material by electroporation [0013]. SEOW demonstrates successfully delivering exogenous genetic material through exosome-mediated delivery to the brain through a series of experiments in C57BL/6 mice [0106].
Regarding claim 14, SEOW teaches exosomes can be produced by many different types of cells including glioma cells, platelets, reticulocytes, neurons, intestinal epithelial cells, and tumour cells [0029]. SEOW teaches exosomes of the invention can be isolated from any suitable cell as listed above, or autologous patient-derived, heterologous haplotype-matched or heterologous stem cells to reduce or avoid an immune response from the patient when the exosomes are delivered [0029][0032]. SEOW also teaches successfully transfecting Neuro2A cells with wild-type exosomes and exosomes expressing RVG-Lamp2B [0022][0023].
Regarding claim 16, WIKLANDER teaches an extracellular vesicle comprising a binding protein, and at least one small molecule agent bound to the binding protein. WIKLANDER also teaches the binding protein can be ICAM1 and the small molecule agent is a drug, selected from anti-cancer agents, DNA or RNA intercalators, kinase inhibitors, tyrosine kinase inhibitors such as BTK inhibitors, many of which are membrane-permeable pharmacotherapeutic compounds, such as testosterone and tamoxifen (Claims 1 and 3 and p. 15).
Regarding claim 18, SEOW teaches modifying an exosome to comprise a targeting moiety expressed on the surface of the exosome which binds to a moiety present on the cell to be targeted, wherein the targeting moiety is expressed as a fusion protein with an exosomal transmembrane protein (Ref. claim 8). SEOW teaches targeting of exosomes to a desired cell type is achieved by expressing a targeting moiety on the surface of the exosomes, and specifically teaches ICAM-1 as an example of an exosomal transmembrane protein to be used to modify the surface of exosomes [0048], (Claim 9). SEOW teaches the targeting moiety is introduced into the exosome by expressing the fusion protein comprising the targeting moiety and exosomal transmembrane protein within a cell used to produce the exosomes, thus allowing the fusion protein to be incorporated into the exosome [0063]. A polynucleotide construct, such as a DNA plasmid, expressing the fusion protein, is transfected into the cell [0064].
Response to Arguments
On p. 5, under the heading “Rejection Under 35 U.S.C. § 103”, third paragraph, Applicant argues that “[n]either Seow nor Klimuk, alone or in combination, teach or suggest producing EVs from fibroblasts expressing recombinant ICAM1 as claimed.”
Applicant’s argument is not persuasive because the composition claims recite a product by process which is not limited by the process but by the product itself. See MPEP 2113. SEOW in view of KLIMUK and WIKLANDER renders the claimed product, which is an EV with an ICAM of SEQ ID NO: 1 from fibroblasts, obvious as discussed in the 103 rejection above.
Previous rejection, maintained: claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over SEOW in view of KLIMUK and WIKLANDER, as applied to claim 1, 3, 14, 16, and 18 above, and further in view of ALEXANDER (WO2016179417 Alexander et al, published November 11, 2016; see PTO-892 of 05/06/2025).
The combined teachings of SEOW and KLIMUK teach an extracellular vesicle comprising ICAM1, comprising the ICAM1 taught by KLIMUK, and further comprising therapeutic cargo which can be genetic material such as miRNA. The combined references do not teach the therapeutic cargo specifically comprises miR146a.
ALEXANDER recites a method of delivering a therapeutic microRNA (miRNA) to a subject, comprising the steps of isolating one or more cells from the subject; harvesting one or more exosomes from the isolated cells; loading the exosomes with the therapeutic miRNA, wherein the therapeutic miRNA is configured to repress a target mRNA; and introducing the miRNA-loaded exosomes into the subject (Claim 1, [0038]). ALEXANDER further teaches that the therapeutic miRNA is miR-146a (Reference claims 20, 21).
It would have been prima facie obvious to a person of ordinary skill in the art to modify an exosome with ICAM1, further comprising a therapeutic cargo as taught by the combined references, wherein the therapeutic cargo is miR146a as taught by ALEXANDER.
One of ordinary skill in the art would have been motivated to and have a reasonable expectation of success given: 1) The combined references teach a modified exosome with ICAM1 for targeted delivery, 2) the combined references teach successfully loading exosomes with therapeutic cargo including miRNA, and 3) ALEXANDER teaches successfully loading exosomes specifically with miR146a for therapeutic delivery.
Response to Arguments
On p. 6, third paragraph, Applicant argues that “[n]oting that Seow and Klimuk do not teach using the EVs to deliver miRNA as the cargo, the Office cites Alexander in an attempt to cure this deficiency. However, Alexander does not cure the deficiencies of Seow and Klimuk described above. None of the cited references teach or suggest producing EVs from fibroblasts displaying ICAM-1 or provide any utility for such an EV with a reasonable expectation of success. ”
Applicant’s argument is not persuasive because the composition claims recite a product by process which is not limited by the process but by the product itself. See MPEP 2113. SEOW in view of KLIMUK and WIKLANDER renders the claimed product, which is an EV with an ICAM of SEQ ID NO: 1 from fibroblasts, as discussed above.
Previous rejection, withdrawn: claims 12, 14, and 18 were rejected under 35 U.S.C. 103 as being unpatentable over US20170182182A1, Seow et al, published June 29, 2017, in view of WO2016179417 Alexander et al, published November 11, 2016.
In view of the claim amendments in the reply of 10/16/2025, this rejection is withdrawn.
Previous rejection, withdrawn: claims 12 and 13 were rejected under 35 U.S.C. 103 as being unpatentable over US20170182182A1, Seow et al, published June 29, 2017, in view of WO2016179417 Alexander et al, published November 11, 2016 as applied to claim 12 above, and further in view of WO1997046671A1, Klimuk et al, published December 1997, as evidenced by UniProt P13597, ICAM1_Mouse (printed April 2025).
In view of the cancelation of claims 12 – 13, this rejection is withdrawn.
Previous rejection, withdrawn: claims 12 and 15 were rejected under 35 U.S.C. 103 as being unpatentable over US20170182182A1, Seow et al, published June 29, 2017, in view of WO2016179417 Alexander et al, published November 11, 2016, as applied to claims 12, 14, and 18 above, and further in view of US20180028600A1, Hong et al, published February 1, 2018 and “Dual effect of oxidative stress on leukemia cancer induction and treatment,” Udensi et al, published December 18, 2014.
In view of the claim amendments in the reply of 10/16/2025, this rejection is withdrawn.
New rejection, necessitated by claim amendments: claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over SEOW in view of KLIMUK and WIKLANDER, as applied to claims 1, 3, 14, 16, and 18 above, and further in view of HONG (US20180028600A1, Hong et al, published February 1, 2018; see PTO-892 of 05/06/2025) and UDENSI (“Dual effect of oxidative stress on leukemia cancer induction and treatment,” UDNESI (Udensi et al, published December 18, 2014; see PTO-892 of 05/06/2025).
The teachings of SEOW and KLIMUK are set forth above. The combined references do not teach the extracellular vesicle further comprises Glut-1.
HONG teaches successfully producing a recombinant exosome, which is obtained from a transfected cell for the expression of the GLUT. A gene construct containing a polynucleotide encoding the GLUT protein, which may be GLUT1, is transfected into cells to obtain the recombinant exosome [0035-0036](Claims 1-4, Figure 1), followed by isolation of the recombinant exosomes from HEK293T cells. HONG also teaches the recombinant exosome further comprises and additional therapeutic agent (Claim 5).
UDENSI teaches reduction of reactive oxygen species and managing oxidative stress can provide a potential therapeutic approach to treating leukemia (Abstract). UDENSI teaches a nutritional supplement has apoptotic effects on leukemic cell lines in part through the down-regulation of GLUT-1 expression which can alter cell metabolism (page 5).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to make an extracellular vesicle decorated with ICAM1 and comprising a therapeutic cargo comprising miR146a, and further comprising Glut-1.
One of ordinary skill in the art would have been motivated to and have a reasonable expectation of success given: 1) SEOW teaches an extracellular vesicle comprising ICAM1, 2) HONG demonstrates successfully generating recombinant exosomes which contain Glut-1, 3) UDENSI provides motivation to target Glut-1 for altering cell metabolism in cancer therapeutics.
Previous rejection, withdrawn: claims 12, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over US20170182182A1, Seow et al, published June 29, 2017, in view of WO2016179417 Alexander et al, published November 11, 2016, as applied to claims 12, 14, and 18 above, and further in view of GB2552774A, Wiklander et al, published February 14, 2018, and “Dual effect of oxidative stress on leukemia cancer induction and treatment,” Udensi et al, published December 18, 2014.
In view of the claim amendments in the reply of 10/16/2025, this rejection is withdrawn.
Conclusion
Claims 1, 3 – 5, 14 – 16, and 18 are rejected.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/PETER J REDDIG/Primary Examiner, Art Unit 1646
APPENDIX
Alignment with SEQ ID NO: 1
RESULT 1
ICAM1_MOUSE
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
ID ICAM1_MOUSE Reviewed; 537 AA.
AC P13597; Q61828;
DT 01-JAN-1990, integrated into UNIPROTKB/Swiss-Prot.
DT 01-JAN-1990, sequence version 1.
DT 27-NOV-2024, entry version 226.
DE RecName: Full=Intercellular adhesion molecule 1;
DE Short=ICAM-1;
DE AltName: Full=MALA-2;
DE AltName: Full=MyD10;
DE AltName: CD_antigen=CD54;
DE Flags: Precursor;
GN Name=Icam1; Synonyms=Icam-1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RC STRAIN=BALB/cJ; TISSUE=Myeloma;
RX PubMed=2573511; DOI=10.1002/j.1460-2075.1989.tb08437.x;
RA Horley K.J., Carpenito C., Baker B., Takei F.;
RT "Molecular cloning of murine intercellular adhesion molecule (ICAM-1).";
RL EMBO J. 8:2889-2896(1989).
RN [2]
RP SEQUENCE REVISION.
RA Takei F.;
RL Submitted (APR-1990) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2479693;
RA Siu G., Hedrick S.M., Brian A.A.;
RT "Isolation of the murine intercellular adhesion molecule 1 (ICAM-1) gene.
RT ICAM-1 enhances antigen-specific T cell activation.";
RL J. Immunol. 143:3813-3820(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6 X CBA; TISSUE=Thymus;
RX PubMed=2762164; DOI=10.1093/nar/17.14.5853;
RA Ballantyne C.M., O'Brien W.E., Beaudet A.L.;
RT "Nucleotide sequence of the cDNA for murine intercellular adhesion
RT molecule-1 (ICAM-1).";
RL Nucleic Acids Res. 17:5853-5853(1989).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=NIH Swiss;
RX PubMed=1362180; DOI=10.1016/s0888-7543(05)80132-6;
RA Ballantyne C.M., Sligh J.E., Dai X.Y., Beaudet A.L.;
RT "Characterization of the murine Icam-1 gene.";
RL Genomics 14:1076-1080(1992).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 4-131.
RX PubMed=1690380;
RA Lord K.A., Hoffman-Liebermann B., Liebermann D.A.;
RT "Complexity of the immediate early response of myeloid cells to terminal
RT differentiation and growth arrest includes ICAM-1, Jun-B and histone
RT variants.";
RL Oncogene 5:387-396(1990).
RN [7]
RP DISRUPTION PHENOTYPE.
RX PubMed=9207125; DOI=10.1073/pnas.94.14.7526;
RA Dong Z.M., Gutierrez-Ramos J.C., Coxon A., Mayadas T.N., Wagner D.D.;
RT "A new class of obesity genes encodes leukocyte adhesion receptors.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:7526-7530(1997).
RN [8]
RP GLYCOSYLATION AT ASN-47; ASN-185; ASN-204; ASN-267; ASN-311; ASN-362;
RP ASN-388; ASN-409 AND ASN-456, LACK OF GLYCOSYLATION AT ASN-469 AND ASN-485,
RP AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=16877748; DOI=10.1093/glycob/cwl032;
RA Otto V.I., Damoc E., Cueni L.N., Schurpf T., Frei R., Ali S.,
RA Callewaert N., Moise A., Leary J.A., Folkers G., Przybylski M.;
RT "N-glycan structures and N-glycosylation sites of mouse soluble
RT intercellular adhesion molecule-1 revealed by MALDI-TOF and FTICR mass
RT spectrometry.";
RL Glycobiology 16:1033-1044(2006).
RN [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-185; ASN-204; ASN-362; ASN-388;
RP ASN-409 AND ASN-469.
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-linked
RT cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Heart, Kidney, Liver, Lung, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: ICAM proteins are ligands for the leukocyte adhesion protein
CC LFA-1 (integrin alpha-L/beta-2). During leukocyte trans-endothelial
CC migration, ICAM1 engagement promotes the assembly of endothelial apical
CC cups through ARHGEF26/SGEF and RHOG activation (By similarity).
CC {ECO:0000250}.
CC -!- SUBUNIT: Homodimer. Interacts with MUC1 and promotes cell aggregation
CC in epithelial cells. Interacts with ARHGEF26/SGEF. Interacts (on T cell
CC side) with CD81, CD247 and CD9 at immunological synapses between
CC antigen-presenting cells and T cells. {ECO:0000250|UNIPROTKB:P05362}.
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P13597-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P13597-2; Sequence=VSP_002518;
CC -!- TISSUE SPECIFICITY: Expressed at low level on a subpopulation of
CC lymphocytes, macrophages, and endothelial cells, but is strongly
CC induced on these cells, and on fibroblasts and epithelial cells.
CC -!- PTM: Monoubiquitinated, which is promoted by MARCH9 and leads to
CC endocytosis. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Spontaneous onset of obesity in 16-week old mice
CC with higher levels of white and brown fat and a slightly heavier liver.
CC Enhanced susceptibility to high fat diet-induced obesity characterized
CC by a weight increase and higher levels of white and brown fat.
CC {ECO:0000269|PubMed:9207125}.
CC -!- SIMILARITY: Belongs to the immunoglobulin superfamily. ICAM family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Functional Glycomics Gateway - Glycan Binding;
CC Note=ICAM-1;
CC URL="http://www.functionalglycomics.org/glycomics/GBPServlet?&operationType=view&cbpId=cbp_mou_Itlect_288";
CC ---------------------------------------------------------------------------
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DR EMBL; X16624; CAA34621.1; -; mRNA.
DR EMBL; X16625; CAA34622.1; -; mRNA.
DR EMBL; M31585; AAA37876.1; -; mRNA.
DR EMBL; X52264; CAA36507.1; -; mRNA.
DR EMBL; M90551; AAA37875.1; -; Genomic_DNA.
DR EMBL; M90546; AAA37875.1; JOINED; Genomic_DNA.
DR EMBL; M90547; AAA37875.1; JOINED; Genomic_DNA.
DR EMBL; M90548; AAA37875.1; JOINED; Genomic_DNA.
DR EMBL; M90549; AAA37875.1; JOINED; Genomic_DNA.
DR EMBL; M90550; AAA37875.1; JOINED; Genomic_DNA.
DR EMBL; X54331; -; NOT_ANNOTATED_CDS; mRNA.
DR CCDS; CCDS22889.1; -. [P13597-1]
DR PIR; A45815; A45815.
DR PIR; I49769; I49769.
DR PIR; S06016; S06016.
DR RefSeq; NP_034623.1; NM_010493.3. [P13597-1]
DR AlphaFoldDB; P13597; -.
DR SMR; P13597; -.
DR DIP; DIP-29096N; -.
DR IntAct; P13597; 1.
DR STRING; 10090.ENSMUSP00000083587; -.
DR GlyCosmos; P13597; 10 sites, No reported glycans.
DR GlyGen; P13597; 10 sites.
DR iPTMnet; P13597; -.
DR PhosphoSitePlus; P13597; -.
DR CPTAC; non-CPTAC-3362; -.
DR jPOST; P13597; -.
DR PaxDb; 10090-ENSMUSP00000083587; -.
DR PeptideAtlas; P13597; -.
DR ProteomicsDB; 269522; -. [P13597-1]
DR ProteomicsDB; 269523; -. [P13597-2]
DR Antibodypedia; 795; 3187 antibodies from 54 providers.
DR DNASU; 15894; -.
DR Ensembl; ENSMUST00000086399.6; ENSMUSP00000083587.5; ENSMUSG00000037405.9. [P13597-1]
DR GeneID; 15894; -.
DR KEGG; mmu:15894; -.
DR UCSC; uc009ojx.1; mouse. [P13597-1]
DR AGR; MGI:96392; -.
DR CTD; 3383; -.
DR MGI; MGI:96392; Icam1.
DR VEuPathDB; HostDB:ENSMUSG00000037405; -.
DR eggNOG; ENOG502S45R; Eukaryota.
DR GeneTree; ENSGT00940000162311; -.
DR HOGENOM; CLU_036160_1_1_1; -.
DR InParanoid; P13597; -.
DR OMA; NLTVYWF; -.
DR OrthoDB; 4014106at2759; -.
DR PhylomeDB; P13597; -.
DR TreeFam; TF333745; -.
DR Reactome; R-MMU-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR Reactome; R-MMU-216083; Integrin cell surface interactions.
DR BioGRID-ORCS; 15894; 5 hits in 80 CRISPR screens.
DR ChiTaRS; Icam1; mouse.
DR PRO; PR:P13597; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; P13597; protein.
DR Bgee; ENSMUSG00000037405; Expressed in right lung lobe and 191 other cell types or tissues.
DR ExpressionAtlas; P13597; baseline and differential.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:MGI.
DR GO; GO:0070062; C:extracellular exosome; IEA:Ensembl.
DR GO; GO:0001772; C:immunological synapse; IDA:UNIPROTKB.
DR GO; GO:0005178; F:integrin binding; ISO:MGI.
DR GO; GO:0007155; P:cell adhesion; IDA:MGI.
DR GO; GO:0033627; P:cell adhesion mediated by integrin; IDA:MGI.
DR GO; GO:1904646; P:cellular response to amyloid-beta; IEA:Ensembl.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IDA:MGI.
DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; IEP:MGI.
DR GO; GO:0061028; P:establishment of endothelial barrier; IEA:Ensembl.
DR GO; GO:0007159; P:leukocyte cell-cell adhesion; IMP:MGI.
DR GO; GO:0022614; P:membrane to membrane docking; IEA:Ensembl.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl.
DR GO; GO:0002693; P:positive regulation of cellular extravasation; IEA:Ensembl.
Query Match 100.0%; Score 2780; Length 537;
Best Local Similarity 100.0%;
Matches 537; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MASTRAKPTLPLLLALVTVVIPGPGDAQVSIHPREAFLPQGGSVQVNCSSSCKEDLSLGL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MASTRAKPTLPLLLALVTVVIPGPGDAQVSIHPREAFLPQGGSVQVNCSSSCKEDLSLGL 60
Qy 61 ETQWLKDELESGPNWKLFELSEIGEDSSPLCFENCGTVQSSASATITVYSFPESVELRPL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ETQWLKDELESGPNWKLFELSEIGEDSSPLCFENCGTVQSSASATITVYSFPESVELRPL 120
Qy 121 PAWQQVGKDLTLRCHVDGGAPRTQLSAVLLRGEEILSRQPVGGHPKDPKEITFTVLASRG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PAWQQVGKDLTLRCHVDGGAPRTQLSAVLLRGEEILSRQPVGGHPKDPKEITFTVLASRG 180
Qy 181 DHGANFSCRTELDLRPQGLALFSNVSEARSLRTFDLPATIPKLDTPDLLEVGTQQKLFCS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DHGANFSCRTELDLRPQGLALFSNVSEARSLRTFDLPATIPKLDTPDLLEVGTQQKLFCS 240
Qy 241 LEGLFPASEARIYLELGGQMPTQESTNSSDSVSATALVEVTEEFDRTLPLRCVLELADQI 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LEGLFPASEARIYLELGGQMPTQESTNSSDSVSATALVEVTEEFDRTLPLRCVLELADQI 300
Qy 301 LETQRTLTVYNFSAPVLTLSQLEVSEGSQVTVKCEAHSGSKVVLLSGVEPRPPTPQVQFT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 LETQRTLTVYNFSAPVLTLSQLEVSEGSQVTVKCEAHSGSKVVLLSGVEPRPPTPQVQFT 360
Qy 361 LNASSEDHKRSFFCSAALEVAGKFLFKNQTLELHVLYGPRLDETDCLGNWTWQEGSQQTL 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 LNASSEDHKRSFFCSAALEVAGKFLFKNQTLELHVLYGPRLDETDCLGNWTWQEGSQQTL 420
Qy 421 KCQAWGNPSPKMTCRRKADGALLPIGVVKSVKQEMNGTYVCHAFSSHGNVTRNVYLTVLY 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 KCQAWGNPSPKMTCRRKADGALLPIGVVKSVKQEMNGTYVCHAFSSHGNVTRNVYLTVLY 480
Qy 481 HSQNNWTIIILVPVLLVIVGLVMAASYVYNRQRKIRIYKLQKAQEEAIKLKGQAPPP 537
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 HSQNNWTIIILVPVLLVIVGLVMAASYVYNRQRKIRIYKLQKAQEEAIKLKGQAPPP 537
RESULT 1
AAW46736
ID AAW46736 standard; protein; 537 AA.
DT 15-JUN-2007 (revised)
DT 02-JUN-1998 (first entry)
DE Amino acid sequence of mouse intercellular adhesion molecule-1.
Inducible; cytokine; overexpression; cellular adhesion molecule; intracellular adhesion molecule-1; ICAM-1; antisense molecule;
lipid mixture; Alzheimer's disease; multiple sclerosis; viral hepatitis;
cholangitis; cardiac allograft rejection; BOND_PC;
intercellular adhesion molecule;
intercellular adhesion molecule [Mus musculus]; Icam1; CD54; Ly-47;
Icam-1; MALA-2; MGC6195; intercellular adhesion molecule 1;
unnamed protein product; unnamed protein product [Mus musculus];
mature ICAM-1 (AA 1-510).
OS Mus sp.
CC PN WO9746671-A1.
CC PD 11-DEC-1997.
CC PF 22-MAY-1997; 97WO-CA000347.
PR 30-MAY-1996; 96US-00657753.
CC PA (UYBR-) UNIV BRITISH COLUMBIA.
CC PI Klimuk SK, Semple SC, Scherrer P, Hope MJ;
DR WPI; 1998-042180/04.
DR N-PSDB; AAV16211.
DR PC:NCBI; gi51508.
DR PC:SWISSPROT; P13597.
SQ Sequence 537 AA;
Query Match 100.0%; Score 2780; Length 537;
Best Local Similarity 100.0%;
Matches 537; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MASTRAKPTLPLLLALVTVVIPGPGDAQVSIHPREAFLPQGGSVQVNCSSSCKEDLSLGL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MASTRAKPTLPLLLALVTVVIPGPGDAQVSIHPREAFLPQGGSVQVNCSSSCKEDLSLGL 60
Qy 61 ETQWLKDELESGPNWKLFELSEIGEDSSPLCFENCGTVQSSASATITVYSFPESVELRPL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ETQWLKDELESGPNWKLFELSEIGEDSSPLCFENCGTVQSSASATITVYSFPESVELRPL 120
Qy 121 PAWQQVGKDLTLRCHVDGGAPRTQLSAVLLRGEEILSRQPVGGHPKDPKEITFTVLASRG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 PAWQQVGKDLTLRCHVDGGAPRTQLSAVLLRGEEILSRQPVGGHPKDPKEITFTVLASRG 180
Qy 181 DHGANFSCRTELDLRPQGLALFSNVSEARSLRTFDLPATIPKLDTPDLLEVGTQQKLFCS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DHGANFSCRTELDLRPQGLALFSNVSEARSLRTFDLPATIPKLDTPDLLEVGTQQKLFCS 240
Qy 241 LEGLFPASEARIYLELGGQMPTQESTNSSDSVSATALVEVTEEFDRTLPLRCVLELADQI 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LEGLFPASEARIYLELGGQMPTQESTNSSDSVSATALVEVTEEFDRTLPLRCVLELADQI 300
Qy 301 LETQRTLTVYNFSAPVLTLSQLEVSEGSQVTVKCEAHSGSKVVLLSGVEPRPPTPQVQFT 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 LETQRTLTVYNFSAPVLTLSQLEVSEGSQVTVKCEAHSGSKVVLLSGVEPRPPTPQVQFT 360
Qy 361 LNASSEDHKRSFFCSAALEVAGKFLFKNQTLELHVLYGPRLDETDCLGNWTWQEGSQQTL 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 LNASSEDHKRSFFCSAALEVAGKFLFKNQTLELHVLYGPRLDETDCLGNWTWQEGSQQTL 420
Qy 421 KCQAWGNPSPKMTCRRKADGALLPIGVVKSVKQEMNGTYVCHAFSSHGNVTRNVYLTVLY 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 KCQAWGNPSPKMTCRRKADGALLPIGVVKSVKQEMNGTYVCHAFSSHGNVTRNVYLTVLY 480
Qy 481 HSQNNWTIIILVPVLLVIVGLVMAASYVYNRQRKIRIYKLQKAQEEAIKLKGQAPPP 537
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 HSQNNWTIIILVPVLLVIVGLVMAASYVYNRQRKIRIYKLQKAQEEAIKLKGQAPPP 537