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 third 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.
Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 13 April 2026 has been entered.
Status of the Claims
Applicant amended claims 85 and 96-98. 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 Claims 85-104 are pending, and claims 103-104 remain withdrawn because they are directed to non-elected Groups II and III, respectively.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 85-102 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 Pharmaceutical research 32.11 (2015): 3526-3540) is withdrawn in view of Applicant’s narrowing amendment to claim 85.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 Tagawa (US 5,264,221) and Jain (“Current ADC linker chemistry.” Pharmaceutical research 32.11 (2015): 3526-3540) is new. The examiner notes that Tagawa is newly cited.
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 has been modified in view of 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double patenting as being unpatentable over claims 84-85 and 88 of co-pending Application No. 18/050,017 is withdrawn in view of Applicant’s narrowing amendment to claim 85.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 90 of co-pending Application No. 17/635,298 is withdrawn in view of 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 claims 1, 4-5, 11-12, 18, and 53 of co-pending Application No. 18/246,304 is new.
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: “wherein the scaffold moiety is enriched in the EV.” In this context, there is ambiguity as to where the boundary lies between enriched and non-enriched. The specification of the present application does not adequately address the following salient issue: What is the difference between (i) an EV that is enriched in the scaffold moiety and (ii) an EV that is not enriched in the scaffold moiety? How would a person having ordinary skill in the art reliably distinguish between those two classes of EV, especially considering there is no baseline (non-enriched) for comparison?
In further regard to claim 85 (as amended), does the phrase “the scaffold moiety” refer only to those scaffold moieties that have a functional group on them that is linked to the cleavable linker via a maleimide moiety? Or, does it instead broadly refer to all scaffold moieties comprised in the EV? This is relevant because it unclear whether the former or the latter is enriched.
In still further regard to claim 85 (as amended), the following phrase is unclear: “wherein the functional group is on a scaffold moiety.” Does this mean the functional group is chemically bonded to the scaffold moiety? In the words, does the phrase require that the functional group and the scaffold moiety are part of the same molecule?
Regarding to claim 96 (as amended), there is ambiguity as to whether this claim requires that the biologically active molecule (BAM) is linked to the luminal/external surface of the EV via the cleavable linker introduced in claim 85. For example, does the claim encompass a configuration wherein the BAM is covalently bonded directly to a scaffold lipid, wherein the scaffold lipid does not include the functional group of claim 85? MPEP § 2173.04 (“a genus claim that could be interpreted in such a way that it is not clear which species are covered would be indefinite (e.g., because there is more than one reasonable interpretation of what species are included in the claim)”).
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 Tagawa (US 5,264,221) 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 bilayer membrane) or, instead, is bonded to the pharmacological agent. As explained below, the following two references compensate for this deficiency: Tagawa and Jain.
Tagawa is directed to a “drug-containing protein-bonded liposome.” Title.
Tagawa teaches: “A drug-containing protein-bonded liposome comprising a liposome containing a drug and having maleimide residues on its surface, and a protein and residues of a compound having a polyalkylene glycol moiety, bonded via respective thiol groups to the maleimide residues.” (Emphasis added) Abstract; see also column 2 (lines 12-17) and column 8 at claim 1.
Tagawa teaches that the bilayer of the liposome comprises maleimide-modified phosphatidyl ethanolamine. Column 2 at lines 45-47.
Tagawa teaches how to synthesize maleimide-modified dipalmitoylphosphatidyl ethanolamine. Columns 5-6 at Example 1.
Tagawa teaches more broadly how to add a maleimide moiety to essentially any compound having an amino group. Column 2 at lines 56-65.
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 Tagawa and Jain would have motivated a person having ordinary skill in the art to add maleimide-modified dipalmitoylphosphatidyl ethanolamine (mal-DPPE) to the bilayer membrane of the extracellular vesicles (EVs) disclosed in Wiklander, thereby yielding maleimide moieties on the vesicular surfaces and facilitating subsequent attachment of the promising cleavable linker taught in Figure 5 of Jain. 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 major 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 claims 32 and 36 of co-pending Application No. 18/248,036 (as amended on May 28, 2026).
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. Conflicting claim 32 discloses that “the ASO is linked to the anchoring moiety on the exterior or luminal surface of the EV.” Emphasis added. Thus, the conflicting claims collectively satisfy claims 85-102 of the present application.
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 1, 4-5, 11-12, 18, and 53 of co-pending Application No. 18/246,304 (as amended on March 10, 2026).
Although the claims at issue are not identical, they are not patentably distinct from each other because of the following: Conflicting claims 1, 4-5, 11-12, and 53 of the ’304 Application are directed to an extracellular vesicle (EV) having an antigen and/or adjuvant attached to its exterior surface or luminal surface via a cleavable linker. Conflicting claim 18 discloses that the linker can comprise a maleimide moiety. Thus, the conflicting claims collectively satisfy claims 85-102 of the present application.
This is a provisional rejection because the conflicting claims have not been patented.
Conclusion
Claims 85-102 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER ANTHOPOLOS whose telephone number is 571-270-5989. The examiner can normally be reached on Monday – Friday (9:00 am – 5:00 pm). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany P. Barham, can be reached on Monday – Friday (9:00 am – 5:00 pm) at 571-272-6175. The fax number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.A./
27 June 2026
/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
Prosecution Insights