DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This is the second Office action on the merits of the claims.
All citations to the Manual of Patent Examining Procedure (MPEP) refer to Revision 01.2024, which was released in November 2024.
Status of the Claims
In the Reply filed 03 November 2025, Applicant amended claims 85-90, 94-97, and 99. Claims 1-84 were cancelled previously by Applicant. Claims 85-104 are pending, and claims 103-104 remain withdrawn because they are directed to non-elected Groups II and III, respectively. Claims 85-102 are under consideration.
Status of the Rejections
The rejection under 35 U.S.C. 112(b) has been modified in view of Applicant’s recent claim amendments.
The rejection of claims 85-90 and 96-102 under 35 U.S.C. 102(a)(1) as being anticipated by Wiklander (WO 2018/011128 A1), as evidenced by HUGO (Symbol Report for ITGB4. HUGO Gene Nomenclature Committee. Accessed 31 July 2025), is withdrawn in view of Applicant’s narrowing amendment to claim 85.
The rejection of claims 91-95 under 35 U.S.C. 103 as being unpatentable over Wiklander (WO 2018/011128 A1) in view of Jain (“Current ADC linker chemistry.” Pharmaceutical research 32.11 (2015): 3526-3540) and Nairn (WO 2019/126240 A1) is withdrawn in view of Applicant’s narrowing amendment to claim 85.
The rejection of claims 85-102 under 35 U.S.C. 103 as being unpatentable over Wiklander (WO 2018/011128 A1) in view of Roberts-Dalton (“Fluorescence labelling of extracellular vesicles using a novel thiol-based strategy for quantitative analysis of cellular delivery and intracellular traffic.” Nanoscale 9.36 (2017): 13693-13706) and Jain (“Current ADC linker chemistry.” Pharmaceutical research 32.11 (2015): 3526-3540) is new and is necessitated by Applicant’s narrowing amendment to claim 85.
The provisional rejection of claims 85-102 on the ground of non-statutory double patenting as being unpatentable over claim 36 of co-pending Application No. 18/248,036 is maintained.
The provisional rejection of claims 85-102 on the ground of non-statutory double patenting as being unpatentable over claims 84-85 and 88 of co-pending Application No. 18/050,017 is maintained.
The provisional rejection of claims 85-102 on the ground of non-statutory double patenting as being unpatentable over claim 90 of co-pending Application No. 17/635,298 is maintained.
All other non-statutory double patenting rejections set forth in the previous Office action (05 August 2025) are withdrawn in view of Applicant’s narrowing amendment to claim 85. The examiner appreciates Applicant’s effort in advancing prosecution.
Claim Rejections - 35 U.S.C. 112(b)
The following is a quotation of 35 U.S.C. 112(b):
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.
Claims 85-102 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter that the inventors regard as the invention.
Regarding claim 85 (as amended), the following new limitation is unclear: “a maleimide moiety linking the cleavable linker to the EV.” The preamble of claim 85 is directed to “[a]n extracellular vesicle (EV).” The manner in which the new limitation is drafted confusingly extends beyond the scope of the preamble by indicating that neither the maleimide moiety nor the cleavable linker are constituents of the EV, itself. The latter even conflicts with language set forth earlier in the claim stating that the EV comprises the cleavable linker. This raises doubt over which elements should be considered part of the EV and, conversely, which should not. For example, does a biologically active molecule (BAM) carried inside the EV actually qualify as a constituent of the EV? If an ADC (antibody-drug conjugate) composed of [BAM]-[maleimide moiety]-[cleavable linker]-[antibody], such as that shown in Figure 12 of Jain (page 3535 at “MCC-linker”), is encapsulated within the lipid bilayer lumen of an EV, is claim 85 satisfied even though there is no covalent bonding between the ADC and the lipid bilayer? Perhaps Applicant is intending to claim that the maleimide moiety covalently anchors the cleavable linker to the EV’s bilayer membrane? This lack of clarity renders claim 85 and all claims depending thereon (claims 86-102) indefinite.
Regarding claim 96, based on Applicant’s recent amendment to claim 85, it does not seem plausible — or consistent with the subject matter that the inventors regard as the invention — that the cleavable linker anchors or otherwise attaches to a scaffold protein or scaffold lipid. If anything, claim 85 suggests that it is the maleimide moiety that fulfills that function. Does claim 96 require that both the maleimide moiety and the cleavable linker directly attach to the scaffold? This lack of clarity renders claim 96 and both claims depending thereon (claims 97 and 98) indefinite.
Claim Rejections - 35 U.S.C. 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 85-102 are rejected under 35 U.S.C. 103 as being unpatentable over Wiklander (WO 2018/011128 A1) in view of Roberts-Dalton (“Fluorescence labelling of extracellular vesicles using a novel thiol-based strategy for quantitative analysis of cellular delivery and intracellular traffic.” Nanoscale 9.36 (2017): 13693-13706) and Jain (“Current ADC linker chemistry.” Pharmaceutical research 32.11 (2015): 3526-3540).
Wiklander is directed to “methods for metabolically loading extracellular vesicles (EVs) with a pharmacological agent.” Abstract.
Wiklander discloses that “the present invention pertains to an EV comprising a pharmacological agent conjugated to a metabolic component.” Page 2.
Wiklander discloses that “[s]uitable metabolic components may include lipids such as phospholipid, peptides, sterols such as cholesterol, vitamins such as vitamin B12, etc.” Page 2. The metabolic component can be a constituent of the EV membrane. Page 24 at claim 10 (“wherein the metabolic component is a lipid, a peptide or a protein, a mono-, di- or polysaccharide, a vitamin, a sterol, a ganglioside, an EV or cell membrane component, or any combination thereof”); see also pages 7-8 at bridging sentence (the metabolic component can be an EV structural component, such as a phospholipid or a cholesteryl moiety).
Wiklander discloses: “The conjugate typically comprises a chemical link between the metabolic component and the pharmacological agent, and this chemical linkage may optionally dissociate, break, release, or get cleaved to release the pharmacological agent. Although advantageous, release of the pharmacological agent from the metabolic component is not a requirement, as long as the pharmacological agent can exert its pharmacological effect while bound to the metabolic component. Suitable non-limiting examples of releasable chemical linkages are disulfide bridges or thioether bonds which may become undergo reduction in reductive environments, amide bonds which may be cleaved by e.g. proteases and other enzymes, biotin-streptavidin linkages which dissociate under certain in vivo conditions, etc. There are nonetheless multiple strategies available for covalent conjugation/linkage of a pharmacological agent to a metabolic component, with nonlimiting examples such as an ester bond, an amide bond, a disulfide bond, a thioether bond, a biotin-streptavidin interaction, a linkage obtained through a maleimide-NHS reaction, a linkage obtained through a EDC-NHS reaction, a stapled linkage (for instance an all-hydrocarbon staple) and various other bonds.” (Emphasis added) Page 10.
Although Wiklander discloses that (i) cleavable linkers are advantageous and (ii) a linkage can be achieved via a maleimide-NHS reaction, Wiklander is silent as to whether the maleimide moiety, itself, is bonded to the metabolic component (e.g., a constituent of the EV membrane) or, instead, is bonded to the pharmacological agent. As explained below, the following two references compensate for this deficiency: Roberts-Dalton and Jain.
Roberts-Dalton is directed to the labelling of extracellular vesicles (EVs) using a thiol-based strategy.
Roberts-Dalton teaches: “The EV is an environment that is cysteine rich, through, for example, the presence of tetraspanin webs. We therefore postulated that the thiol (–S–H groups) present on these structures would react with a maleimide functional group, to form a stable, non-reversible, thio-ether linkage.” (Emphasis added) Page 13696, right column.
Jain is directed to linkers used in antibody-drug conjugates.
Jain teaches: “Maleimide chemistry has been the mainstay for linkage to cysteines. Two common variants are the maleimidocaproyl (mc) and maleimidomethyl cyclohexane-1-carboxylate (mcc). Also illustrated is the self-stabilizing maleimide construct designed to prevent early release of the cytotoxin via retro-Michael reaction.” (Emphasis added) Page 3530 at caption of Figure 4.
Jain teaches several linkers that include both a maleimide moiety and a cleavable group. See, e.g., Figure 5 (p. 3531), Figure 6 (page 3532), and Figure 7 (page 3533). Figure 5, for example, is reproduced on the next page:
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Jain teaches: “The construct utilizes a maleimidocaproyl (mc) spacer, a protease-sensitive dipeptide, valine-citrulline (vc), a self-immolative spacer, para-amino benzyloxycarbonyl (PABC), and the antimitotic agent, monomethyl auristatin E (MMAE) as illustrated in Fig. 5. The purpose of the mc spacer is to provide enough room so that the vc group can be recognized by cathepsin B, which cleaves the citrulline-PABC amide bond. The resultant PABC-substituted MMAE is not a stable intermediate and spontaneously undergoes a 1,6-elimination with a loss of p-iminoquinone methide and carbon dioxide (self-immolation) leaving MMAE as the product. The optimization of this design was an evolutionary process which entailed much experimentation. This design was successfully used in ADCETRIS®, an anti-CD30-vc-MMAE construct, for relapsed Hodgkin lymphoma.” Page 3530.
Jain additionally teaches that the vc-MMAE linker-drug combination is being used in thirteen clinical trials for ADCs, including even a Phase 3 trial. Page 3530 at Table I.
Before the effective filing date of the claimed invention, the foregoing teachings of Roberts-Dalton and Jain would have motivated a person having ordinary skill in the art to modify Wiklander by reacting the maleimide moiety of any of the corresponding linkers taught in Jain with the cysteine-rich EV membrane. This modification would have been made to yield a thioether bond, which is relatively stable under physiological conditions, between the linker and the metabolic constituent of the EV membrane, thereby promoting the structural integrity of the EV, while advantageously allowing for the versatility of tailored or physiologically-specific release of the pharmacological agent provided by the cleavable moiety in the remainder of the linker. Therefore, claim 85 is prima facie obvious.
Regarding claims 86-87 and 90-92, Applicant is referred to Figure 5 of Jain (page 3531).
Regarding claims 88 and 89, Wiklander discloses: “Suitable non-limiting examples of releasable chemical linkages are disulfide bridges or thioether bonds which may become undergo reduction in reductive environments….” (Emphasis added) Page 10. Jain teaches: “The third release strategy exploits the higher concentrations of intracellular glutathione than in the plasma. Thus, linkers containing a disulfide bridge release the cytotoxin upon reduction by glutathione.” Page 3529, left column.
Regarding claims 93 and 94, Figure 5 of Jain shows there is a C5 alkyl spacer between the maleimidocaproyl (mc) and valine-citrulline (vc) moieties.
Regarding claim 95, Jain teaches that “[t]he purpose of the mc spacer is to provide enough room so that the vc group can be recognized by cathepsin B, which cleaves the citrulline-PABC amide bond.” Page 3530, right column; see also Figure 5. In Figure 8 (page 3533), Jain shows a diethylene glycol spacer, which is close enough to a tetraethylene glycol spacer to support a finding of prima facie obviousness. MPEP § 2144.05(I) (“a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close”); MPEP § 2144.05(II)(A) (“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”).
Regarding claims 96-98, Wiklander discloses that “the metabolic component is a lipid, a peptide or a protein, a mono-, di- or polysaccharide, a vitamin, a sterol, a ganglioside, an EV or cell membrane component, or any combination thereof.” Page 24 at claim 10; see also pages 7-8 (bridging paragraph). Wiklander identifies ITGA4 as an exemplary protein that can be selected as the metabolic component. Page 8. Wiklander discloses: “Other non-limiting examples of lipids include phospholipids, sphingolipids, glycolipids, cholesterol and other sterols, mono-, di- or tri-glycerides.” Page 8. The examiner notes that the EV membrane has two surfaces: the interior (luminal) surface and the exterior surface, and claim 96 encompasses both those surfaces.
Regarding claim 99, Wiklander identifies “antisense oligonucleotides” as exemplary pharmacological agents. Page 7; see also page 24 at claim 9.
Regarding claim 100, Wiklander discloses that the EV can further comprise a “targeting moiety.” Page 24 at claim 11; see also pages 13-14 (bridging paragraph).
Regarding claim 101, Wiklander discloses: “The terms ‘extracellular vesicle’ or ‘EV’ or ‘exosome’ are used interchangeably herein and shall be understood to relate to any type of vesicle that is obtainable from a cell in any form, for instance a microvesicle (e.g. any vesicle shed from the plasma membrane of a cell), an exosome (e.g. any vesicle derived from the endo-lysosomal pathway), an apoptotic body (e.g. obtainable from apoptotic cells), a microparticle (which may be derived from e.g. platelets), an ectosome (derivable from e.g. neutrophils and monocytes in serum), prostatosome (e.g. obtainable from prostate cancer cells), or a cardiosome (e.g. derivable from cardiac cells), etc.” (Emphasis added) Page 6.
Regarding claim 102, Wiklander identifies “carrier” as a suitable excipient for pharmaceutical compositions that comprise the EVs disclosed therein. Page 14.
Claim Rejections - Double Patenting (Non-Statutory)
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminalDisclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/ eTD-info-I.jsp.
Claims 85-102 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claim 36 of co-pending Application No. 18/248,036 (as preliminarily amended on October 6, 2023).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following: Conflicting claim 36 of the ’036 Application is directed to an EV comprising a biologically active molecule (i.e., an ASO) and a linker that can comprise both a maleimide moiety and a cleavable group, which can be Val-Cit-PABC or Val-Ala-PABC. See limitations (vi), (viii), and (ix) of claim 36. This is a provisional rejection because the conflicting claims have not been patented.
Claims 85-102 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 84-85 and 88 of co-pending Application No. 18/050,017 (as amended on December 23, 2025).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following: Conflicting claims 84-85 and 88 of the ’017 Application are directed to an exosome (EV) comprising a biologically active molecule (i.e., an ASO) and a linker that can comprise both a maleimide moiety and a cleavable group, which can be Val-Cit-PABC, Val-Ala-PABC, etc. This is a provisional rejection because the conflicting claims have not been patented.
Claims 85-102 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claim 90 of co-pending Application No. 17/635,298 (as amended on September 11, 2025).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following: Conflicting claim 90 of the ’298 Application is directed to an EV comprising a biologically active molecule (i.e., an ASO) and a linker that can comprise the following combination: (i) a maleimide moiety and (ii) Val-Cit-PABC or Val-Ala-PABC. This is a provisional rejection because the conflicting claims have not been patented.
Conclusion
Claims 85-102 are rejected.
No claim is allowed.
Applicant’s amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/P.A./
07 February 2026
/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
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