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 .
Notice of Pre-AIA or AIA Status
DETAILED ACTION
Status of the Claims
Claims 3-112, 117-119, 121, 123-127, 129-132, 134-135, 137-147, 149-210, 212-230, 237-240, and 242-245 are cancelled. Claims 1-2, 113-116, 120, 122, 128, 133, 136, 148, 211, 231-236, and 241 are pending. Claims 113 and 234-236 and 241 are withdrawn. Claims 1-2, 114-116, 120, 122, 128, 133, 136, 148, 211 and 231-233 are under examination.
Priority
This application is a national stage entry of PCT/EP2022/059940 filed on 4/13/2022, which claims priority from US provisional application 63/174,874 filed on 4/14/2021.
Information Disclosure Statement
The information disclosure statement filed on 10/13/2023 has been considered by the examiner.
Election/Restriction
Applicant’s election without traverse of Group I (claims 1-2, 114-116, 120, 122, 128, 133, 136, 148, 211 and 231-233 in the reply filed on 10/28/2025 is acknowledged.
Claims 113 and 234-236 and 241 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/28/2025. This is treated without traverse as applicant did not traverse the restriction portion of the requirement.
In regards to the species election for an amino acid and corresponding nucleic acid sequence that corresponds to a polypeptide of the claims, the applicant traverses on the grounds that a sequence that encompasses all the domains was not determined in the specification. Applicant instead claims based on domains of the polypeptide including an ephrin receptor cysteine rich domain, ephrin receptor FN III domains, and a generic transmembrane domain along with support of specification and prior art described mutations and/or deletions that would cause the kinase activity and/or ephrin binding activity to be lacking. The examiner will withdraw the species election in light of applicant’s inability to elect species as was asked with considering this polypeptide having certain ephrin receptor domains and a transmembrane domain.
Specification Objections
The use of the terms tribody, monobody, Fynover, avimer, anticalin, affilin, affibody, probody, DARPin, Centyrin, nanofitin, adnectin, nanobody and DVD-Ig (found in the USPTO trademark search database), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term where applicable.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1-2, 114, 120, 122, 148, and 211 are objected to for using periods after the lettering “a, b, c…” where a parentheses may be used instead. Usually only one period is allowed in the claim (at the end of the claim).
Claim 116 is objected to for “sdAb (VHH or nanobody)” as these are just repeats of the same item (synonyms). Only one item is needed and the others can be deleted.
Claims 128, 133 and 148 are objected to for the recitation of “SBD” for the first time without first spelling it out. SBD is noted as “scaffold binding domain” in applicant’s specification (paragraph 13).
Claim 148 is objected to for recitation of “SAM” for the first time without first spelling it out. SAM is noted as “sterile α-motif” in applicant’s specification (paragraph 32).
Claim 148 is objected to for recitations of “JM” and “KD” without first spelling them out. KD is kinase domain and JM is juxtamembrane domain (see paragraph 403 of specification).
Appropriate corrections are required.
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, 2, 114-115, 120, 122, 128, 133, 136, 148, 211, and 231-233 rejected under 35 U.S.C. 101 because the claimed invention is directed to products of nature. The claim(s) recite(s) naturally occurring ephrin proteins with naturally occurring domains of ephrin proteins and also ephrin proteins with natural isoforms or mutations/deletions that will cause lack of kinase activity and/or ephrin binding activity. Claim 1 provides for these receptors which are naturally transmembrane proteins to be present in exosomes, which are naturally secreted vesicles by cells and will contain such receptors that are present within the membrane including ephrin receptors. Claim 2 is to a hybridosome (an exosome combined with a liposome, liposomes are just lipid vesicles that can be made up of naturally occurring lipids) that carries the naturally occurring protein. There is no other structure or compositional feature of the hybridosome that provides markedly different characteristics to the ephrin polypeptide in the claim. Claim 231 reads on the genomic DNA of a cell that has ephrin receptors and claim 233 reads on a cell having its DNA. Although claim 232 is to an expression vector, it is not specialized in any way and would only have to be a carrier for the naturally occurring sequence. Liang et al (Biochem J, 2021, volume 478, pages 3351-3371) teaches EphB6 and EphA10 which are pseudokinase members of the Eph receptor family where they were characterized to have the biochemical properties and topology of the EphB6 and EphA10 intracellular regions comprising the juxtamembrane (JM) region, pseudokinase and SAM domains (abstract). Liang finds that the pseudokinase domains of EphB6 and EphA10 lack conserved catalytic residues (Results of Liang and figure 1). Liang provides these ephrin receptor pseudokinases bind nucleotides through their pseudokinase domains (a cargo binding domain) (see Results, EphB6 and EphA10 pseudokinase domains bind nucleotides). EphB6 was tested for kinase activity but had no basal phosphorylation (page 3362 of Liang). In figure 3, EphB6 has an intracellular domain with SAM domains and PBM (PDZ domain binding motif). Arora et al (Biomedicines, 2023, volume 11, pages 1-24) teaches an Eph receptors (abstract). Arora teaches different domains of Eph receptors including extracellular portion with cysteine rich/abundant domain, two FN III domains, a transmembrane domain and an intracellular domain that can have kinase domain, SAM domain and PDZ binding motif (figure 1 of Arora). Section 2 of Arora breaks down structure and signaling of Eph Receptors (starts on page 1). Arora also mentions the pseudokinases in section 6, which have the same general architecture but are catalytically dysfunctional (page 12 section 6). Arora provides that PDZ binding motifs allow for interaction with PDZ domain containing proteins (page 3). Additionally, SAM domains promote the engagement of SH2-domain containing proteins (page 3). Arora also notes that Eph receptors are found to be mutated in cancers that can alter Ephrin receptor functions (section 5.3 and abstract). Although mutations to Eph binding domains are not discussed, the entire Ephrin receptor sequence is prone to natural mutations or deletions that can affect various abilities. Cancer mutations in the Eph binding domain are discussed by Lisabeth et al (Cold Spring Harb Perspect Biol, 2013, volume 5, pages 1-20) in Gene Mutations (pages 12-13). Thus, activity altering mutations occur in Ephrin receptors. Thus, such mutations occur naturally to Eph receptor kinases and pseudokinases. In regards to claim 122, the targeting domain may be the ephrin binding domain that targets ephrins. In regards to linker in claim 128, this may be the amino acids leading up to the domain such as kinase domain, SAM domain or PDZ binding motif that attach it to the protein. In regards to claim 133, the SBD linked to the cargo protein is not a limitation of the polypeptide being claimed as it refers to the cargo protein. In regards to claim 136, this is a characteristic of the binding domain of the polypeptide (protein) toward the cargo protein and it is known that changing pH and/or ionic strength is capable of interfering with protein binding due to effects on amino acids and/or protein folding. As Ephrin receptors are noted in Lisabeth et al as being expressed by genes in cells, they are encoded by DNA (DNA – RNA – protein). The insertion of natural genes into vectors (routine in the art) or production of hybridosomes with natural exosomes having naturally occurring proteins as in claims 2 and 232 does not significantly alter the products of nature (the gene, protein or the exosome). Although hybrid exosomes (hybridosomes) are engineered exosomes, they are meant to be exosome-like and claim 2 does not provide features of a hybridosome that would significantly alter an exosome from its naturally occurring state or it also does not incorporate an item that is not naturally occurring (see Mondal et al (Journal of Controlled Release, 2023, volume 353, pages 1127-1149) regarding hybrid exosome development and exosomes). In this way, hybridosome relates to the process of making it (i.e.. engineering an exosome to what is considered some hybrid state for some purpose (e.g. drug carrier, etc)). Features would have to be incorporated into the claim for the hybridosome to have markedly different characteristics from a natural exosome (the naturally occurring vesicle) or alternatively the protein of the hybridosome in claim 2 would have to carry limitations that provide it markedly different characteristics from natural ephrin receptors.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 114-116, 120, 122, 128, 133, 136, 148, 211 and 231-233 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claims 1, 2, 114, 120, 122 and 148 as well as their dependent claims include a polypeptide comprising in the N-terminus to C-terminus direction, an ephrin receptor cysteine-rich (CR) domain, a first and a second ephrin receptor fibronectin type III domain and a transmembrane domain with claims also adding items like cargo protein or cargo binding domain at the C-terminal portion, and targeting domain at the N-terminal portion. In addition, other linker domains or SBD domains may be present. Targeting domains that only have to be N-terminal compared to the CR domain are provided broadly as various types of antibodies, antibody fragments or peptides/polypeptides capable of binding antigens, but does not provide sequences for such items where this would determine a binding functionality of the polypeptide. As the polypeptide comprises such domains with only order being dictated, it allows for variable amounts and types of other sequence to be present between domains or at the N-terminal and C-terminal ends of the polypeptide. Each of these new sequences allowed by the claims even if containing domains listed will represent a new polypeptide with new possible functionality, which allows the claims to encompass many varying polypeptides having numerous functionalities or even no functionality. It is noted that example 1 (section 7.1) of applicant’s specification provides for a polypeptide that is monobody-linker1-modified monomeric Fc-linker2-EphB2 scaffold-linker3-turboluc with EphB2 scaffold comprised residues 195-905 of EphB2, lacking a LBD, and containing the following amino acid substitutions L356A, I395A, S536E, A562S, Y822F relative to SEQID NO:222. Paragraph 483 provides for another polypeptide that is anti-EphA2 scFv-linker-EphB4 fragment as detailed in paragraph 483 with lacking LBD and amino acid substitutions which is then linked to the endodomain of EphA2 as provided therein. These versions of polypeptides have particular types of targeting domains at the N-terminus directly attached to a linker that is directly attached to an Ephrin receptor that has been modified in a particular way in the examples (these also start with a given domain and then end with a given domain, where applicant’s claims would allow the N-terminus and C-terminus to extend with other sequence). Thus, there are a limited amount of specialized domain sequences with linkers described in the polypeptides that are exemplified by applicants in their disclosure, which have the purpose of targeting exosomes or hybridosomes to a target area. However, the applicant does not have written description for all the possible polypeptides of various sequences and sizes the claims would allow due to “comprising” and with the domains, which although ordered from N-terminus to C-terminus, could be spaced apart with various sequences of different lengths including other functional sequences in between. That is, the polypeptide represents a vast genus of possible polypeptides of which applicant only describes and shows ownership for a limited few being made in examples with particular domains and structure. This creates the same issue for the polynucleotide that is supposed to encode the polypeptide. Applicant should consider amending the claims to be more in scope with described examples of polypeptides provided by applicant with limiting the polypeptide with “consisting of” or starting with what particular domain is at the N-terminal end of the polypeptide and laying out each domain directly connected to each next portion finishing with a definite domain or sequence at the C-terminal end.
Claim Rejections - 35 USC § 112(b)
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 116 and 211 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.
Claims 116 contain the trademark/trade names (as found in the USPTO Trademark search) tribody, monobody, Fynover, avimer, anticalin, affilin, affibody, probody, DARPin, Centyrin, nanofitin, adnectin, nanobody and DVD-Ig. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe different antibodies, antibody fragments, peptides or polypeptides that bind to antigens, and, accordingly, the identification/description is indefinite.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 116 recites the broad recitation monobody, and the claim also recites (or adnectin) (adnectin is a type of monobody, but also note a trademark/brand name) which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 211 is indefinite for the recitation of “modified Fc domain of an immunoglobulin” as it is unclear what type of modification that the applicant is referring to for the claim. Modified Fc domain is not particularly defined in the specification. Therefore, it is unclear what the metes and bounds of modified Fc domain will be to read on the claim. For the purpose of compact prosecution, if the prior art provides an Fc domain with any type of modification, it will read on the limitation. Applicant may consider amending the claim to provide what “modified” refers to or may consider deleting “modified” from the claim.
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.
Claim(s) 114-115, 120, 122, 128, 133, 136, 148, 211, and 231-233 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Freywald et al (JBC, 2002, volume 277, pages 3823-3828) as evidenced by Arora et al (Biomedicines, 2023, volume 11, pages 1-24).
Applicant’s claimed invention depends mainly on polypeptide with a transmembrane domain and a portion of an N-terminal extracellular domain with ephrin receptor domains where a targeting domain can be attached to (made to be part of the polypeptide). Other claims of applicant also allow for intracellular domains to be present.
The limitation of “comprising in an N-terminus to C-terminus direction”, means that although the items following this will be present in this order, there can be sequence that can occur in before or after and in between these domains/sequences.
The limitation of a “cargo protein or cargo binding domain” as being a polypeptide domain that is either linked to the polypeptide structure that can be a protein/polypeptide itself or one that is capable of binding other proteins or “cargo”. The limitation does not present for a structure that the cargo must have besides being a protein or binding domain.
The limitation of “linker” is read as a sequence or other compound capable of linking one item to the next. Amino acid sequence or functional groups/bonds between domains can be construed as linking them together.
The limitation of “targeting domain” will be read as a domain capable of binding/targeting to an organ, cell or tissue in the body. This would include binding of a cell bound ligand such as an ephrin (ephrins are attached to cells). The specification does not limit targeting domain to only antibodies or antibody fragments. Paragraph 401 provides this regarding “targeting domain” – “a targeting domain that is capable of targeting the nanovesicle (e.g., EV or hybridosome) to a specific organ, tissue, or cell type).”
Claims 133 and 136 are toward characteristics between the cargo binding domain and the cargo protein. Where the prior art teaches a protein domain capable of binding other proteins or SBD (scaffold binding domain) of another protein, if the prior art teaches protein domains that act to bind other proteins, directly or indirectly, they will seen as being capable of control by pH or ionic strength as they are protein/protein interactions. Note also that the claim is not toward a method of using for such protein binding and is read for the characteristics/structure of the claimed polypeptide itself.
Freywald teaches kinase null EphB6 receptor (title and abstract). Freywald teaches subcloning EphB6 into an expression vector that is transfected into cells (Experimental Procedures and Results). Freywald provides that EphB6 binds c-Cbl (figure 6). Freywald provides that the structure of EphB6 is typical of other Ephrin receptors (Discussion). Arora evidences that Eph receptors have ligand binding domain, cysteine abundant region, two FN III domains, a transmembrane domain, a juxtamembrane region, a SAM domain and a PDZ binding motif (figure 1 of Arora, Arora indicates EphB6 in section 5.2 and table 1 and section 6). Arora evidences that “EphB6 and EphA10 share the same general architecture as the rest of the Eph RTK family members but are catalytically dysfunctional because of alterations in key residues
that are essential for their tyrosine kinase activities” (section 6 of Arora). Thus, Arora evidences the protein structure that EphB6 had at the time of Freywald. In regards to claims
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 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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Freywald et al (JBC, 2002, volume 277, pages 3823-3828) and Pasquale (JCB, 2016, volume 214, pages 5-7) as evidenced by Seiradake et al (Nat Struct Mol Biol, 2013, volume 20, pages 1-19).
Freywald teaches the claims as discussed above with teachings of the polypeptides of the claims. Seiradake evidences the structure of ephrin receptors with “All Eph receptors share a conserved domain composition1 (Fig. 1a). The ectodomain comprises an N-terminal ligand-binding domain (LBD), a cysteine rich region, which can be divided into a sushi domain and an epidermal-growth-factor-like domain (EGF), followed by two fibronectin type III domains (FN1 and FN2). A single transmembrane helix connects to the intracellular tyrosine kinase domain and a sterile-alpha motif (SAM) domain that can carry a C-terminal PDZ binding motif. Likewise the ephrins are characterized by the conserved architecture of an N-terminal receptor-binding-domain (RBD).” (page 2 of Seiradake).
Freywald does not teach exosomes.
Pasquale teaches exosomes expand the sphere of influence of Eph receptors and ephrins (title and abstract). Pasquale teaches that Ephrin receptors can be deployed by cells on exosomes to activate ephrinB signaling (abstract). Pasquale teaches “Exosomes show promise as cell-derived vehicles for delivery of therapeutic agents (György et al., 2015) and Gong et al. (2016) demonstrate preferential binding of EphB2-positive exosomes to cells expressing ephrinB1, followed by exosome internalization. Thus, it may be possible to take advantage of the Eph system for targeted delivery of therapeutic exosomes to cancer cells or other diseased cells overexpressing Eph receptors/ephrins as well as for promoting exosome uptake by recipient cells” (page 7 of Pasquale). Thus, it was recognized by Pasquale as possible to use ephrin receptors on exosomes for the purpose of drug delivery.
Therefore, it was obvious to one of ordinary skill in the art before the time of filing that ephrin receptors like EphB6 would be able to be carried in exosomes for signaling by the combined teachings of the references with Freywald teaching an Eph receptor that meets the limitation of the claims and Pasquale teaching the presence of expressed Eph receptors in exosomes from cells. Pasquale also recognizes a use of exosomes with Ephrin receptors for targeted delivery of therapeutic exosomes to cancer or other diseased cells making Ephrin receptors a reasonable choice for such targeted exosomes. Thus, there was a reasonable expectation of success in combining the teachings of the references and obtaining exosomes with Eprhin receptors including those like EphB6 (a recognized Ephrin receptor).
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Freywald et al (JBC, 2002, volume 277, pages 3823-3828), Pasquale (JCB, 2016, volume 214, pages 5-7) and Sato et al (Scientific Reports, 2016, DOI: 10.1038/srep21933, pages 1-11) as evidenced by Seiradake et al (Nat Struct Mol Biol, 2013, volume 20, pages 1-19).
Freywald and Pasquale teach the claims as discussed above. Pasquale teaches “Exosomes show promise as cell-derived vehicles for delivery of therapeutic agents (György et al., 2015) and Gong et al. (2016) demonstrate preferential binding of EphB2-positive exosomes to cells expressing ephrinB1, followed by exosome internalization. Thus, it may be possible to take advantage of the Eph system for targeted delivery of therapeutic exosomes to cancer cells or other diseased cells overexpressing Eph receptors/ephrins as well as for promoting exosome uptake by recipient cells” (page 7 of Pasquale).
Freywald and Pasquale does not teach hybridosomes (a modified form of exosome).
Sato also recognizes the use of exosomes as biomaterials for use as nanocarriers for drug delivery systems (abstract and figure 1). Sato teaches hybrid exosomes made by fusing them with liposomes (abstract). Sato recognizes these methods of producing hybrid exosomes (hybridosomes) is strategy for rationally designing exosomes as nanocarriers for drug delivery systems (abstract and Discussion).
One of ordinary skill in the art before the time of filing would be able to form hybrid exosomes from exosomes including those with Ephrin receptors, which also are recognized as useful for delivery of therapeutic agents, in order to be used for drug delivery systems by the combined teachings of the references. Thus, there was a reasonable expectation of success in combining the teachings of the references to obtain hybrid exosomes (membrane engineered exosomes) that have Eprhin receptors for drug (therapeutic) delivery systems.
Claim 116 is rejected under 35 U.S.C. 103 as being unpatentable over Freywald et al (JBC, 2002, volume 277, pages 3823-3828), Pasquale (JCB, 2016, volume 214, pages 5-7) and Wiklander US20200109183A1 as evidenced by Seiradake et al (Nat Struct Mol Biol, 2013, volume 20, pages 1-19).
Freywald and Pasquale teach the claims as discussed above. Pasquale teaches “Exosomes show promise as cell-derived vehicles for delivery of therapeutic agents (György et al., 2015) and Gong et al. (2016) demonstrate preferential binding of EphB2-positive exosomes to cells expressing ephrinB1, followed by exosome internalization. Thus, it may be possible to take advantage of the Eph system for targeted delivery of therapeutic exosomes to cancer cells or other diseased cells overexpressing Eph receptors/ephrins as well as for promoting exosome uptake by recipient cells” (page 7 of Pasquale).
Freywald and Pasquale does not teach attaching an antibody, antibody fragment or targeting peptide/polypeptide to the Eph receptors on exosomes.
Wiklander teaches extracellular vesicle (EV) therapeutics, wherein the EVs are coated with proteins containing Fc domains (such as antibodies) for i.e. targeting and therapeutic applications (abstract and figure 1). Figure 1 of Wiklander provides an Fc binder domain attached/linked to an exosomal transmembrane protein in the lipid bilayer of an exosome (also paragraphs 10-11 and 14). Wiklander teaches “Such therapeutic protein and/or peptide agents may be selected from a group of non-limiting examples including: antibodies, intrabodies, single chain variable fragments (scFv), affibodies, bi- and multispecific antibodies or binders, affibodies, darpins, receptors…” (paragraph 28). Wiklander teaches Fc domain containing receptors or ligands (paragraph 31). Wiklander’s figure 1 shows the Fc binder domain attached to the extraexosomal end of the protein, which for ephrin receptors will be the N-terminal portion placed before the cysteine rich domain. Wiklander mentions any C and/or N terminal direction with the fusion proteins (paragraphs 39-42). Wiklander provides for linkers in its teachings (paragraph 34).
One of ordinary skill in the art before the time of filing would have produced ephrin receptor exosomes as motivated by Freywald and Pasquale and further modified the Ephrin receptors as being an available transmembrane receptor with Fc domains for improved targeting of therapeutic exosomes in the body by teachings of Wiklander. Thus, there was a reasonable expectation of success in combining the teachings of the references to produce ephrin receptors conjugated/attached to Fc domains for better targeting of exosomes they are bound to in order to reach new targets in the body, where exosomes are recognized for use to carry drugs for targeted delivery.
Conclusion
No claims are allowed.
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/MARK V STEVENS/Primary Examiner, Art Unit 1613