DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Species A (i.e., A single and specific isolated extracellular vesicle including indication of: 1. A single and specific biologically active molecule, Applicants’ Election: a peptide; 1a. A single and specific location of the biologically active molecule, Applicants’ Election: in the lumen of the EV; 2. A single and specific scaffold protein, indicating single and specific SEQ ID NO to which biologically active molecule is linked, Applicants’ Election: GGKLSKKK (SEQ ID NO: 161); 2a. If more than one scaffold protein, a single and specific polypeptide comprised within the second scaffold protein, Applicants’ Election: PTGFRN; 2b. A single and specific N-terminus domain (ND) comprised within the scaffold protein, indicating single and specific SEQ ID NO, Applicants’ Election: GGKLSK (SEQ ID NO: 203); 2c. A single and specific effector domain (ED) comprised within the scaffold protein, indicating single and specific SEQ ID NO, Applicants’ Election: KK; 2d. Whether the scaffold protein comprises a transmembrane domain and if so, relationship with respect to the biologically active molecule and effector domain, Applicants’ Election: the scaffold protein does not comprise a transmembrane domain), in the reply filed on 02/13/2025 is acknowledged.
Claims 28 and 39-40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/13/2025.
Please note that claim 29 has been rejoined and it is under consideration. The claim dependency has been amended to depend from instant claim 1.
Newly submitted claims 83-88 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: The claims are directed to multiple categories of inventions. For instance, a polynucleotide, a chemical compound, a virus (i.e., adeno-associated virus, a parvovirus, a retrovirus, an adeno virus or any combination thereof), an ionophore or a carrier for an ionophore, a molecule that forms a channel or a pore, an inhibitor for a negative checkpoint regulator or an activator for a positive co-stimulatory molecule.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim83-88 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
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 12/16/2025 has been entered.
Status of Claims
Claims 1-82 were originally filed on 05/13/2021.
The amendment filed on 02/14/2022, cancelled claims 2-6, 8-16, 19-27, 31-33, 35-37, 41-42, 44-45, 47, 49-51, 55-72, 75-80 and 82; and amended claims 1, 7, 17, 18, 28-30, 34, 38-40, 43, 46, 48, 52, 54, 73-74 and 81.
The amendment filed on 08/07/2025, cancelled claims 17-18, 39-40, 54 and 81; amended claims 1, 34, 38, 48, 53 and 74; and added new claims 83-88.
The amendment filed on 11/17/2025, cancelled claim 38, amended claims 1 and 48; and added new claim 88.
Claims 1, 7, 29-30, 34, 43, 46, 48, 52-53, 73-74 and 88 are pending and under consideration.
Priority
The present application claims status as a 371 (National Stage) of PCT/US2019/033629 filed May 22nd 2019, which claims the benefit under 35 U.S.C 119(e) to U.S. Provisional Application No. 62/835,430 filed April 17th 2019; and is a CON of PCT/US18/61679 filed November 16th 2018, which claims the benefit under 35 U.S.C 119(e) to U.S. Provisional Application No. 62/634,750 filed February 23rd 2018; and claims the benefit under 35 U.S.C 119(e) to U.S. Provisional Application No. 62/587,767 filed November 17th 2017.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, CON of PCT/US18/61679 filed November 16th 2018, which claims the benefit under 35 U.S.C 119(e) to U.S Provisional Application No. 62/634,750 filed February 23rd 2018; and claims the benefit under 35 U.S.C 119(e) to U.S. Provisional Application No. 62/587,767 filed November 17th 2017, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. In the instant case, the disclosure of the prior-field applications fail to provide adequate support/enablement for an isolated extracellular vesicle comprising a biologically active molecule linked to a scaffold protein, wherein the scaffold protein comprises an N-terminus domain (ND) and an effector domain (ED) […] wherein the ND comprises the amino acid sequence GGKLSK (SEQ ID NO: 203), but does not comprise a methionine (Met) at the N-terminus. Additionally, MPEP 2173.05(i) states that any negative limitation or exclusionary proviso must have basis in the original disclosure. Therefore, since the prior-filed applications fail to provide adequate disclosure/written description of the isolated extracellular vesicle comprising the amino acid sequence GGKLSK (i.e., SEQ ID NO: 203) without the Methionine at the N-terminus; claims 1, 7, 17-18, 30, 34, 38, 43, 46, 48, 52-54, 43, 46, 48, 52-54, 73-74 and 81 are not entitled to the benefit of the prior-filed applications, CON of PCT/US18/61679 filed November 16th 2018, which claims the benefit under 35 U.S.C 119(e) to U.S Provisional Application No. 62/634,750 filed February 23rd 2018; and claims the benefit under 35 U.S.C 119(e) to U.S. Provisional Application No. 62/587,767 filed November 17th 2017.
Sequence Interpretation
Regarding claim 1, please note that the Examiner is interpreting the scope the N-terminus domain in the scaffold protein as open-ended requiring 100% identity to SEQ ID NO:203, with any N-/C-terminal additions.
Regarding claim 7, please note that the Examiner is interpreting the scope of the effector domain (ED) in the scaffold protein as open-ended requiring 100% identity to KK, with any N-/C- terminal additions.
Response to Arguments
1. Applicants’ arguments, see Remarks, filed 11/17/2025, with respect to the drawings have been fully considered and are persuasive. The Objections to Fig. 16A and Fig. 16B have been withdrawn.
2. Applicants’ arguments, see Remarks, filed 11/17/2025, with respect to 35 U.S.C. 103 as being unpatentable over US2018/0015182 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”) in view of Sperlich et al., Biophysical Journal 111, 2016, 113-122 (herein after “Sperlich”); and Merchant et al., Nat Rev Nephrol. 2017; 13(12); 731-749 (herein after “Merchant”); have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection to claims 1, 7, 29-30, 34, 48, 52-53, 73 and 89 has been maintained.
3. Applicants’ arguments, see Remarks, filed 11/17/2025, with respect to 35 U.S.C. 103 as being unpatentable over US2018/0015182 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”) in view of Sperlich et al., Biophysical Journal 111, 2016, 113-122 (herein after “Sperlich”), as applied to claim 1, and further in view of Prasad et al., Journal of Peptide Science, 2007; 13: 458-467 (herein after “Prasad”) as applied to claims 43 and 46; have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection to claims 43 and 46 has been maintained.
4. Applicants’ arguments, see Remarks, filed 11/17/2025, with respect to 35 U.S.C. 103 as being unpatentable over US2018/0015182 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”) in view of Sperlich et al., Biophysical Journal 111, 2016, 113-122 (herein after “Sperlich”); and further in view of WO 2018/039119 A1 with International Publication Date of March 1st 2018 (herein after “Williams”); have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection to claim 74 has been maintained.
5. Applicants’ arguments, see Remarks, filed 11/17/2025, with respect to the Double Patenting rejection over claims 1-4, 6-8, 14, 15-16 and 19 of U.S. Patent No. US 11679164 (herein after “164” in view of US2018/0015282 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”); Merchant et al., Nat Rev Nephrol. 2017; 13(12); 731-749 (herein after “Merchant”); and Prasad et al., Journal of Peptide Science, 2007; 13: 458-467 (herein after “Prasad”); have been fully considered, but are not persuasive. The nonstatutory double patenting rejection of claims 1, 43, 46, 48, 52-53 and 73-74 has been maintained.
6. Applicants’ arguments, see Remarks, filed 11/17/2025, with respect to the Double Patenting rejection over claims 1, 9-11, 15 and 25 of copending Application No. 18/057,709 (McConnell et al. US Publication No. 2024/0000944 A1) in view of US2018/0015282 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”); Sperlich et al., Biophysical Journal 111, 2016, 113-122 (herein after “Sperlich”); Merchant et al., Nat Rev Nephrol. 2017; 13(12); 731-749 (herein after “Merchant”); and WO 2018/039119 A1 with International Publication Date of March 1st 2018 (herein after “Williams”); have been fully considered, but are not persuasive. The nonstatutory double patenting rejection of claims 1, 48, 52-53 and 74 has been maintained.
7. Applicants’ arguments, see Remarks, filed 11/17/2025, with respect to the Double Patenting rejection over claims 1, 4 and 10-14of U. S. Patent No. 10,561,740 (Dooley et al. Date of Patent Feb. 18, 2020) in view of WO 2018/039119 A1 with International Publication Date of March 1st 2018 (herein after “Williams”), Merchant et al., Nat Rev Nephrol. 2017; 13(12); 731-749 (herein after “Merchant”), and US2018/0015282 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”); have been fully considered but are not persuasive. The nonstatutory double patenting rejection of claims 1, 48, 53 and 74 has been maintained.
Maintained/Modified Rejections in light of Amendments
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
1. Claims 1, 7, 29-30, 34, 48, 52-53, 73 and 89 are rejected under 35 U.S.C. 103 as being unpatentable over US2018/0015182 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”) in view of Sperlich et al., Biophysical Journal 111, 2016, 113-122 (herein after “Sperlich”); and Merchant et al., Nat Rev Nephrol. 2017; 13(12); 731-749 (herein after “Merchant”).
Regarding claim 1, Lu teaches engineered exosomes for the delivery of bioactive cargo, where the exosomes incorporate a tetraspanin transmembrane anchoring scaffold onto the membrane of the exosome (see Abstract). The tetraspanin transmembrane anchoring scaffold has a C-terminal attachment site in the inner-vesicle space of the exosome, a N-terminal attachment site in the inner-vesicle space (see Abstract). Lu teaches that peptides can be attached to the different attachments sites in any form or combination (see Abstract). Tetraspanins naturally anchor on the exosome membrane, are biocompatible, and allow for robust loading and delivery of bioactive cargos in mammalian system (see Abstract). Lu also teaches that exosomes are lipid-bilayer-enclosed extracellular vesicles that transport signaling proteins, nucleic acids, and lipids among cells (see pg. 2, para[0017]); and that the tetraspanin transmembrane anchoring scaffold could have a first terminal attachment site in the inner-vesicle space (see pg. 5, para[0041]). A first protein 610 in FIG. 6A, could be attached to the C-terminal attachment site of the tetraspanin transmembrane anchoring scaffold right before the stop codon so that the first peptide is located in the inner-vesicle space (see pg. 5, para[0041] and FIG. 6A). Therefore, the teachings of Lu et al. constitutes an extracellular vesicle comprising a biologically active molecule linked to the C-terminus of a scaffold protein in the inner-vesicle space.
However, Lu does not expressly teach wherein the scaffold protein comprises an N-terminus domain (ND) and an effector domain (ED), wherein the ND is associated with the luminal surface of the EV and the ED is associated with the luminal surface of the EV by an ionic interaction, wherein the ND comprises the amino acid sequence GGKLSK (SEQ ID NO: 203), and wherein the ED comprises a lysine (Lys) at its N-terminus that is linked directly to the lysine at the C-terminus of SEQ ID NO: 203 in the ND.
Sperlich teaches regulation of K-Ras4B membrane binding by calmodulin (see pg. 113, Title). More specifically, Sperlich teaches that the Ca2+ binding calmodulin (CaM) is known to function as a potential binding partner for farnesy-related Ras proteins (see pg. 113, Abstract). Sperlich teaches the crystal structure of the Ca2+/CaM in complex with a myristoylated peptide, the peptide consisting of GGKLSK (i.e., SEQ ID NO: 203) is located along the groove between two lobes of Ca2+/CaM (see pg. 114, FIG. 1 Description). Sperlich also teaches that the C-terminal basic cluster of the myristoylated peptide, i.e., GGKLSK, is KKK (i.e., myr-GGKLSKKKK) (see pg. 114, left column, paragraph 1); and that that the N-terminal myristoyl group was found to be firmly anchored to Ca2+/CaM by multiple hydrophobic interactions, i.e., it is accommodated in a large hydrophobic cavity created by the hydrophobic pockets in the N- and C-terminal domains of Ca2+/CaM (see pg. 114, left column, first paragraph). As such, Sperlich teachings read on wherein the scaffold protein is about 7 to about 30 amino acids in length as recited in instant claim 1.
From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the tetraspanin transmembrane anchoring scaffold in the engineered exosomes for the delivery of bioactive cargo of Lu with the Ca2+ binding calmodulin (CaM) in complex with a myristoylated peptide of Sperlich in order to arrive at the claimed scaffold protein comprising an N-terminus domain (ND) and an effector domain (ED) as recited in instant claim 1. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because Sperlich’s CaM complex with a myristoylated peptide consists of the peptide GGKLSK (i.e., SEQ ID NO: 203). One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that N-terminal myristoyl group is accommodated in a large hydrophobic cavity created by the hydrophobic pockets in the N- and C-terminal domains of Ca2+/CaM; and because the calmodulin (i.e., Ca2+/CaM) regulates membrane binding of proteins. Therefore, substituting the CaM complex with a myristoylated peptide consisting of the peptide GGKLSK taught by Sperlich as part of the engineered exosomes for the delivery of bioactive cargo of Lu would support a scaffold protein comprising an N-terminus domain (ND) and an effector domain (ED), wherein the ND is associated with the luminal surface of the EV and the ED is associated with the luminal surface of the EV by an ionic interaction, wherein the ND comprises the amino acid sequence GGKLSK (SEQ ID NO: 203), and wherein the ED comprises a lysine (Lys) at its N-terminus that is linked directly to the lysine at the C-terminus of SEQ ID NO: 203 in the ND; by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or the simple substitution of one known element for another to obtain predictable results, pursuant to KSR.
Regarding claim 7, Sperlich teaches that the C-terminal basic cluster of the myristoylated peptide, i.e., GGKLSK, is KKK (i.e., myr-GGKLSKKKK) (see pg. 114, left column, paragraph 1); thereby constituting wherein the ED comprises KK (i.e., Applicants’ Election). As such, the teachings of Lu when combined with the teachings of Sperlich suggest wherein the ED comprises KK as recited in instant claim 7.
Regarding claims 29-30 and 34, Sperlich teaches that the myristoylated peptide, i.e., myr-GGKLSKKKK, which constitutes the scaffold protein of instant claim 1, is 9 amino acids in length and also the N-terminus of the myristoylated peptide is Gly (see pg. 114, left column, paragraph 1). Therefore, the teachings of Sperlich satisfy the claim limitations as recited in instant claims 29-30 and 34.
Regarding claim 48, Lu teaches that by tagging a therapeutic protein on the inner surface of exosomes, one may devise new-exosome-based therapeutics with the use of the exosome surface display system (see pg. 1, para[0006]). Lu also teaches that examples of the first peptide are: an imaging protein, a protein drug, a suicide protein, an enzyme for replacement therapy (see pg. 5, para[0042]). As such, the teachings of Lu constitute wherein the biologically active molecule comprises a protein, selected from the group consisting of (ii) an enzyme, as recited in instant claim 48.
Regarding claims 52 and 53, Lu teaches that a second peptide could be attached to the N-terminal attachment site of the tetraspanin transmembrane anchoring scaffold so that the second peptide is located in the inner-vesicle space or in the outer-vesicle space (see pg. 5, para[0043]) and FIG 6A & 6B). Examples of the second peptide are: a 6xHis tag for detection and purification, an imaging protein, a viral antigen epitope, a cancer antigen epitope, a single chain antibody, or a protein drug (see pt. 5, para[0044]). However, Lu does not expressly teach wherein the second scaffold protein comprises a PTGFRN polypeptide as recited in instant claim 53.
Merchant teaches that extracellular vesicles are lipid-enclosed structures that can be classified into three categories: exosomes, microvesicles (or ectosomes) and apoptotic bodies and that during their formation, urinary extracellular vesicles incorporate various cell-specific components (proteins, lipids and nucleic acids) that can be transferred to target cells (see pg. 1, Abstract). Merchant adds that exosomes display many of the surface markers from their cell of origin (see pg. 3, paragraph 2). The composition of exosomes varies according to their cell of origin; however, owing to their endosomal origin, exosomes also contain a number of abundant proteins, including those involved in membrane transport and fusion (GTPases, annexins and flotillins) and multivesicular body biogenesis (ALIX, TSG101 and clathrin), as well as tetraspanins (CD9, CD63, CD81 and CD82)40–42, heat shock proteins (HSC70 and HSP90)12,43, integrins and RAB proteins that regulate docking and membrane fusion of exosomes with target cells (see pg. 3, paragraph 2). Merchant also teaches that prostaglandin F2 receptor negative regulator (PTGFRN) is a membrane protein that is known to be shed in extracellular vesicles in the blood (see pg. 10, bottom of paragraph 1).
Therefore, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the second peptide attached to the N-terminal attachment site of the tetraspanin transmembrane anchoring scaffold of Lu with the prostaglandin F2 receptor negative regulator (PTGFRN) is membrane protein of Merchant in order to arrive at the claimed EV further comprising PTGFRN as a second scaffold protein. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because PTGFRN is a membrane protein that is known to be a cell specific component that is known to be incorporated into urinary extracellular vesicles, and is also known to be shed in extracellular vesicles in the blood; and because cell specific components can be transferred to target cells as taught by Merchant. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that engineered exosomes for the delivery of bioactive cargo incorporate peptides that can be attached to the different attachment sites of the transmembrane anchoring scaffold as taught by Lu. Therefore, substituting substitute the second peptide attached to the N-terminal attachment site of the tetraspanin transmembrane anchoring scaffold of Lu with the prostaglandin F2 receptor negative regulator (PTGFRN) is membrane protein of Merchant would support an EV further comprising PTGFRN as a second scaffold protein by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or the simple substitution of one known element for another to obtain predictable results, pursuant to KSR.
Regarding claim 73, Lu teaches that exosomes are lipid-bilayer-enclosed extracellular vesicles that transport signaling proteins, nucleic acids, and lipids among cells (see pg. 2, para[0017]). Thereby constituting wherein the EV is an exosome as recited in instant claim 73.
Regarding claim 89, As previously discussed, Sperlich teaches the myristolated peptide GKLSKKKK, which reads on the scaffold protein recited in instant claim 1. Additionally, Sperlich peptide does not comprise methionine (Met) at the N-terminus, therefore it also reads on the claim limitations recited in instant claim 89. In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 USC 103.
2. Claims 43 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over US2018/0015182 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”) in view of Sperlich et al., Biophysical Journal 111, 2016, 113-122 (herein after “Sperlich”) as applied to claim 1 above, and further in view of Prasad et al., Journal of Peptide Science, 2007; 13: 458-467 (herein after “Prasad”) as applied to claims 43 and 46 herewith.
See discussion of Lu in view of Sperlich et al. above.
Regarding claims 43 and 46, Lu teaches that peptides can be attached to the different attachments sites in any form or combination (see Abstract). However Lu does not expressly teach wherein the scaffold protein is linked to the biologically active molecule by a linker as recited in instant claim 43, nor wherein the linker comprises a cleavable linker as recited in instant claim 46.
As previously discussed, Sperlich teaches the C-terminal basic cluster of the myristoylated peptide i.e., myr-GGKLSKKKK, consists of KKK(see pg. 114, left column, paragraph 1).
Prasad teaches delivering multiple anticancer peptides as a single prodrug using lysyl-lysine as a facile linker (see pg. 458, Title). Prasad’s work consists of peptides that are linked together using a linker consisting of pairs of basic amino acids such as Lys-Lys to form a propeptide (see pg. 458, right column, paragraph 2). Prasad adds that most peptides in the human body are synthesized as large precursors or propeptides and undergo endoproteolytic cleavage at pairs of basic residues (i.e., Lys-Lys) (see pg. 458, left column, paragraph 2). Therefore, the teachings of Sperlich when combined with the teachings of Prasad suggest the claim limitations are recited in instant claims 43 and 46 wherein the scaffold protein is linked to the biologically active protein by a cleavable linker (i.e., KK).
Additionally, even if Sperlich did not expressly teach that the myristoylated peptide (i.e., myr-GGKLSK) comprises a linker and the linker comprises a cleavable linker, since Sperlich teaches the C-terminal basic cluster of the myristoylated peptide which comprises KK (i.e., myr-GGKLSKKKK); thereby constituting a well-known linker, the functional properties (i.e., cleavable linker) of the linker as claimed and the known C-terminal basic cluster of the myristoylated peptide (i.e., KKK) would necessarily read upon the same. The discovery of a previously unappreciated property of a prior art composition, or a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of new functional properties (i.e., cleavable linker) which would necessarily read upon the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 4333 (CCPA 1977).
Therefore, before the effective filing date of the claimed invention; the claimed invention would have been prima facie obvious to one of ordinary skill in the art because it was known that engineered exosomes comprise a transmembrane anchoring scaffold such as a myristoylated peptide; and it was also known that the C-terminal basic cluster of the myristolated peptide comprises a lysyl-lysine cleavable linker. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to arrive at the claimed invention because the cargo (e.g., a biologically active molecule) in the engineered exosomes is bound to a transmembrane anchoring scaffold (e.g., myristoylated peptide) via a linker (i.e., lysyl-lysine cleavable linker). One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that the engineered exosomes of Lu are used to deliver bioactive cargos such as peptides; and given that the C-terminal basic cluster of the myristoylated peptide, consists of KKK (i.e., myr-GGKLSKKKK). Therefore, incorporating the C-terminal basic cluster of the myristoylated peptide as part of the engineered exosomes for the delivery of bioactive cargo would support the EV of claim 1 wherein the scaffold protein is linked to the biologically active molecule by a linker and wherein the linker comprises a cleavable linker by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or the simple substitution of one known element for another to obtain predictable results, pursuant to KSR.
3. Claims 74 is rejected under 35 U.S.C. 103 as being unpatentable over US2018/0015182 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”) in view of Sperlich et al., Biophysical Journal 111, 2016, 113-122 (herein after “Sperlich”) as applied to claim 1 above; and further in view of WO 2018/039119 A1 with International Publication Date of March 1st 2018 (herein after “Williams”) as applied to claim 74 herewith.
See discussion of Lu in view of Sperlich et al. above.
Regarding claim 74, Lu teaches engineered exosomes for the delivery of bioactive cargo, wherein the active cargo can be a peptide attached to a transmembrane anchoring scaffold (see Lu, Abstract). However, Lu does not expressly teach a pharmaceutical composition comprising the EV of claim 1 and a pharmaceutically acceptable carrier.
Williams teaches improved methods and compositions for the systemic delivery of therapeutic exosomes to a subject in need thereof, wherein the method involves a suitable therapeutic dose of exosomes with a therapeutic payload (see Abstract). Williams adds that pharmaceutical compositions of the invention can comprise, in addition to one or more of the exosomes, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art (see pg. 40, para[00186]). Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on the route of administration, e.g., oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intrathecal or intraperitoneal routes (see pg. 40, para[00186]). Therefore the teachings of Lu when combined with the teachings of Williams suggest a pharmaceutical composition comprising the EV and a pharmaceutically acceptable carrier.
The Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate a pharmaceutically acceptable excipient, carrier, buffer or a stabilizer as taught by Williams as part of a pharmaceutical composition comprising the engineered exosomes of Lu in order to arrive at the claimed pharmaceutical composition comprising the EV of claim 1. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because compositions for the systemic delivery of therapeutic exosomes are known to comprise a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art and are exosomes are also known to carry a therapeutic payload. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that engineered exosomes for the delivery of bioactive cargo were known and because it was also known that the active cargo can be a peptide attached to a transmembrane anchoring scaffold. Therefore, incorporating engineered exosomes for the delivery of bioactive cargo as taught by Lu as part of the methods and compositions for the systemic delivery of therapeutic exosomes of Williams would support the claimed pharmaceutical composition comprising EV of claim 1 and a pharmaceutically acceptable carrier by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or the simple substitution of one known element for another to obtain predictable results, pursuant to KSR.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed EV. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Double Patenting
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 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); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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 eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
4. Claims 1, 43, 46, 48, 52-54, 73-74 and 81 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8, 15-16 and 19 of U.S. Patent No. US 11679164 (herein after “164”) in view of US2018/0015282 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”); Merchant et al., Nat Rev Nephrol. 2017; 13(12); 731-749 (herein after “Merchant”); and Prasad et al., Journal of Peptide Science, 2007; 13: 458-467 (herein after “Prasad”).
‘164 a method of preparing a composition comprising exosomes, comprising transfecting a producer cell with a nucleotide sequence encoding a scaffold protein, wherein the scaffold protein comprises a PTGFRN, or a fragment or a variant thereof; further comprising isolating the exosomes that are produced; and wherein the scaffold protein is a fusion protein comprising a PTGFRN (see column 157, claims 1-3). It would have been obvious to one of ordinary skill in the art, at the time the invention was made, to have transfected human embryonic kidney cells (HEK293) as taught by Lu, with a fusion protein comprising the PTGFRN surface marker displayed by urinary extracellular vesicles of Merchant to the myristoylated peptide, i.e., myr-GGKLSK of Sperlich, to produce the engineered exosome for the delivery of bioactive cargo as taught by Lu; thereby resulting in an isolated extracellular vesicle comprising a biologically active molecule linked to a scaffold protein, wherein the scaffold protein comprises a N-terminus domain (ND) and an effector domain (ED) as recited in instant claim 1; and wherein the EV further comprises a second scaffold protein as recited in instant claim 52; wherein the second scaffold protein comprises a PTGFRN as recited in instant claim 53; and wherein the EV is an exosome as recited in instant claim 73.
‘164 also claims that the polypeptide sequence comprises a therapeutic protein, a targeting moiety, or any combination thereof (see column 157, claims 4 and 6). Additionally, that the therapeutic protein is fused to the scaffold protein (see column 158, claim 8); and that an exosome comprising a scaffold protein which comprises a PTGFRN, or a fragment or a variant thereof, is used in a method of treating a disease in a subject in need thereof (see column 158, claim 15). It would have been obvious to one of ordinary skill in the art, at the time the invention was made, to have used a lysyl-lysine cleavable linker as taught by Prasad to attach myristoylated peptide, i.e., myr-GGKLSK of Sperlich to the PTGFRN of Merchant, thereby resulting in an EV wherein the scaffold protein is linked to the biologically active molecule by a linker as recited in instant claim 43; wherein in the linker comprises a cleavable linker as recited in instant claim 46; and wherein the biologically active molecule comprises a protein as recited in instant claim 48.
‘164 also claims a pharmaceutical composition comprising the exosome and an excipient (see column 158, claim 16). One of ordinary skill in the art at the time the invention was made, would have incorporated administering a therapeutically effective amount of exosomes comprising a pharmaceutically acceptable excipient or carrier as taught by Williams with the engineered exosome for the delivery of bioactive cargo of Lu, thereby resulting a pharmaceutical composition comprising the EV of claim 1 and a pharmaceutically acceptable carrier as recited in instant claim 74. Therefore, ‘164 claimed invention is not patentably distinct from the instantly claimed invention.
This is a provisional nonstatutory double patenting rejection.
5. Claims 1, 48, 52-53 and 74 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9-11, 15 and 25 of copending Application No. 18/057,709 (McConnell et al. US Publication No. 2024/0000944 A1) in view of US2018/0015282 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”); Sperlich et al., Biophysical Journal 111, 2016, 113-122 (herein after “Sperlich”); Merchant et al., Nat Rev Nephrol. 2017; 13(12); 731-749 (herein after “Merchant”); and WO 2018/039119 A1 with International Publication Date of March 1st 2018 (herein after “Williams”).
McConnell claims an exosome comprising a fusion protein, wherein the fusion protein comprises a biologically active payload and a scaffold protein, wherein the scaffold protein comprises MARCKS, MARCKSL1, BASP1 or a fragment or a modification thereof (see pg. 41, claim 1). It would have been obvious to one of ordinary skill in the art, at the time the invention was made, to substitute the anchoring scaffold in the engineered exosomes for the delivery of bioactive cargo of Lu with the Ca2+ binding calmodulin (CaM) in complex with a myristoylated peptide of Sperlich in order to arrive at the claimed EV comprising a biologically active molecule linked to a scaffold protein, wherein the scaffold protein comprises an N-terminus domain (ND) and an effector domain (ED) as recited in instant claim 1.McConnell’s claims 9-11 recite that the exosome of claim 1, wherein the biologically active payload comprises a therapeutic peptide (see pg. 42, claim 9); wherein the therapeutic peptide comprises a natural peptide, a recombinant peptide, or a synthetic peptide (see pg. 42, claim 10); and that the biologically active payload comprises (i) nucleotides, amino acids, lipids, carbohydrates, or small molecules; (ii) an antibody or a fragment of an of an antibody or a modification thereof; (iii) an enzyme, a ligand, a receptor, a transcription factor, or a fragment or a modification thereof; (iv) an antimicrobial peptide or a fragment or a modification thereof; or (v) any combination of (i)-(iv) (see pg. 42, claim 11). It would have been obvious to one of ordinary skill in the art, at the time the invention was made, to fuse a therapeutic protein on the inner surface of exosomes to devise new-exosome-based therapeutics with the use of the exosome surface display system of Lu in order to arrive at the instantly claimed EV wherein the biologically active molecule comprises a protein as recited in instant claims 1. Lu also teaches that examples of the peptide are: an imaging protein, a protein drug, a suicide protein, an enzyme for replacement therapy. Therefore an ordinary skill artisan would have been motivated with reasonable expectation of success at the time the invention was made to follow the teachings of Lu in order to arrive at the claimed EV wherein the biologically active molecule comprises a protein as recited in instant claim 48.
McConnell’s claim 15 recites that the exosome further comprises a second fusion protein, wherein the second fusion protein comprises MARCKS, MARCKSL1, BASP1, PTGFRN, BSG, IGSF2, IGSF3, IGSF8, ITGB1, ITGA4, SLC3A2, ATP transporter or a fragment thereof (see pg. 42, claim 15). Lu also teaches that a second peptide could be attached to the N-terminal attachment site of the tetraspanin transmembrane anchoring scaffold so that the second peptide is located in the inner-vesicle space or in the outer-vesicle space. Additionally, Merchant teaches that prostaglandin F2 receptor negative regulator (PTGFRN) is a membrane protein that is known to be shed in extracellular vesicles in the blood, and that exosomes display many of the surface markers from their cell of origin. As such, it would have been obvious to an ordinary skilled artisan at the time the invention was made to combine the teachings of Lu with those of Williams to arrive at the claimed EV, wherein the EV further comprises a second scaffold protein as recited in instant claim 52; and wherein the second scaffold protein comprises a PTGFRN as recited in instant claim 53.
Claim 25 of McConnell’s invention recites a pharmaceutical composition comprising the exosome and an excipient, wherein the composition is substantially free of nucleic acids, exogenous proteins, lipids, carbohydrates, metabolites, and a combination thereof (see pg. 42, claim 25). Williams teaches improved methods and compositions for the systemic delivery of therapeutic exosomes to a subject in need thereof, wherein the method involves a suitable therapeutic dose of exosomes with a therapeutic payload. Williams also teaches that the pharmaceutical compositions can comprise, in addition to one or more of the exosomes, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art; and that such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. Therefore an ordinary skilled artisan at the time the invention was made would have been motivated with reasonable expectation of success to arrive at the claimed pharmaceutical composition comprising the EV of instant claim 1 and a pharmaceutically acceptable carrier as recited in instant claim 74. Therefore, McConnell’s claimed invention is not patentably distinct from the instantly claimed invention.
This is a provisional nonstatutory double patenting.
6. Claims 1, 48, 53 and 74 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4 and 10-14of U. S. Patent No. 10,561,740 (Dooley et al. Date of Patent Feb. 18, 2020) in view of WO 2018/039119 A1 with International Publication Date of March 1st 2018 (herein after “Williams”), Merchant et al., Nat Rev Nephrol. 2017; 13(12); 731-749 (herein after “Merchant”), and US2018/0015282 A1 Pub. Date: Jan. 18, 2018 (here in after “Lu”);
Dooley claims a pharmaceutical composition comprising: a. an exosome comprising a scaffold protein, which comprises prostaglandin F2 Receptor Negative Regulator (PTGFRN) or a functional fragment thereof, and: b. an excipient (see column 157, claim 1). It would have been obvious to one of ordinary skill in the art, at the time the claimed invention was made, to follow the teachings of Williams and deliver therapeutic exosomes as part of a pharmaceutical composition also comprising an excipient, a carrier, buffer, stabilizer or other materials well known to those skilled in the art to a subject in need thereof; wherein the exosomes comprise a therapeutic payload. One of ordinary skill in the art at the time the claimed invention was made would have also found it obvious to incorporate the teachings of Merchant and use PTGFRN as a membrane protein in the therapeutic exosomes of Williams; thereby arriving at the claimed EV comprising a biologically active molecule linked to a scaffold protein as recited in instant claim 1; wherein the EV comprises a PTGFRN polypeptide as recited in instant claim 53; and wherein the EV of claim 1 is comprised within a pharmaceutical composition and a pharmaceutically acceptable carrier as recited in instant claim 74.
Dooley also claims that the pharmaceutical composition of claim 1, wherein the exosome further comprises a therapeutic protein (see column 157, claim 4); wherein the therapeutic protein is selected from the group consisting of: (a) an antibody or an antigen-binding fragment thereof, (b) an enzyme or a functional fragment thereof (c) a ligand or a functional fragment thereof, (d) a receptor or a functional fragment, (e) an antimicrobial peptide or a functional fragment, (f) a functional fragment of any of (a)-(e), or (g) any combination of(a)-(f) (see column 158, claim 10); wherein the therapeutic protein is fused to the scaffold protein (see column 158, claim 11); wherein the exosome further comprises a therapeutic compound (see column 158, claim 12); wherein the therapeutic compound is selected from the group consisting of a nucleotide, an amino acid, a lipid, a carbohydrate, a small molecule, and any combination thereof (see column 158, claim 13); and wherein the therapeutic compound is conjugated to the scaffold protein (see column 158, claim 14).
It would have been obvious to one of ordinary skill in the art, at the time the claimed invention was made to combine the teachings of Williams with the teachings of Lu and tag a therapeutic protein on the inner surface of exosomes, one may devise new-exosome-based therapeutics with the use of the exosome surface; and that some examples of the peptide are an imaging protein, a protein drug, a suicide protein, an enzyme for replacement therapy; a 6xHis tag for detection and purification, an imaging protein, a viral antigen epitope, a cancer antigen epitope, a single chain antibody, or a protein drug. As such, at the time the claimed invention was made; it would have been obvious to combine the teachings of Williams with those of Lu in order to arrive at the claimed EV comprising a biologically active molecule linked to a scaffold protein; wherein the biologically active molecule comprises a protein as recited in instant claim 48. Therefore, Dooley’s claimed invention is not patentably distinct from the instantly claimed invention.
This is a provisional nonstatutory double patenting.
Applicants’ Arguments
Applicants assert that none of the cited references recite the EV of claim 1, and that a POSA would not have had a reason to modify nor a reasonable expectation of success in achieving the claimed invention by modifying Lu in view of Sperlich and Merchant (see Remarks, filed 11/17/2025, pg. 9, paragraph 2). Applicants add that Sperlich (whom teaches instant SEQ ID NO: 203) cannot be combined with Lu, at least because (i) Lu already states that “tetraspanins in general can serve as a robust molecular scaffold to display different proteins on exosomes in cultured HEK293 cells” and therefore teaches away from modifying such as scaffold; and (ii) that there is no motivation or rationale provided for one of ordinary skill in the part to modify the transmembrane scaffolds in Lu with the intracellular CaM protein in Sperlich (see Remarks, filed 11/17/2025, pg. 9, last paragraph). Applicants reiterate that there is no motivation to combine Lu with Sperlich and Merchant due to lack of evidence taught in the prior art that the substitution would result successful and/or effective and that there is impermissible hindsight from knowledge of the invention itself (see Remarks, filed 11/17/2025, pg. 10 and pg. 11). Lastly, Applicants assert that the claimed composition proves unexpected results (see Remarks, filed 11/17/2025, pg. 12).
Response to Arguments
Applicant's arguments filed 11/17/2025 with respect to the 35 U.S.C. 103 rejections, have been fully considered but they are not persuasive for the following reasons:
As previously stated in the Office Action mailed on 09/17/2025, obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Additionally, there is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004).
In the instant case, as discussed above in the 35 U.S.C. 103 rejections, the cited prior art is suggestive of the claim limitations as recited in instant claim 1, and dependent claims 7, 29-30, 34, 43, 46, 48, 52-53, 73-74 and 89. Lu expressly teaches engineered exosomes for the delivery of bioactive cargo, where the exosomes incorporate a tetraspanin transmembrane anchoring scaffold onto the membrane of the exosome. Lu also teaches that the tetraspanin transmembrane anchoring scaffold could have a first terminal attachment site in the inner-vesicle space where the first protein could be attached to the C-terminal attachment site of the tetraspanin transmembrane anchoring scaffold right before the stop codon so that the first peptide is located in the inner-vesicle space therefore constituting an extracellular vesicle comprising a biologically active molecule linked to a scaffold protein as recited in instant claim 1. Sperlich teaches that the Ca2+ binding calmodulin (CaM) is known to function as a potential binding partner for farnesy-related Ras proteins and that the crystal structure of the Ca2+/CaM in complex with a myristoylated peptide, the peptide consisting of GGKLSK is located along the groove between two lobes of Ca2+/CaM. Sperlich teachings pertain to regulation of K-Ras4B membrane binding by calmodulin, where the binding protein calmodulin is known to function as potential binding. Therefore an ordinary skilled artisan would have been motivated to substitute the tetraspanin transmembrane anchoring scaffold in the engineered exosomes for the delivery of bioactive cargo of Lu with the Ca2+ binding calmodulin (CaM) in complex with a myristoylated peptide of Sperlich in order to arrive at the claimed scaffold protein comprising an N-terminus domain (ND) and an effector domain (ED) as recited in instant claim 1.
Additionally, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, Applicants assert that the cited art does not disclose the scaffold protein of claim 1 nor demonstrate the effectiveness of the construct, nor identify the problem solved by applicant (see Remarks, filed 11/17/2025, pg. 10, paragraph 2). However, the Examiner maintains that the combination of Lu and Sperlich does not represent “impermissible hindsight”. Rather, because Lu’s engineered exosomes that incorporate a tetraspanin transmembrane anchoring scaffold to the membrane of the exosome, and Sperlich’s peptide consisting of GGKLSK were well known in the art, it would have been obvious to substitute the tetraspanin transmembrane anchoring scaffold of Lu with the GGKLSK peptide of Sperlich.
Furthermore, pursuant to MPEP § 2144, a difference in objectives, if any, does not defeat the case for obviousness because the “reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. In re Linter, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) …; In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) …” As such, the reason an ordinary skilled artisan would substitute the tetraspanin in Lu with GGKLSK peptide in Sperlich does not preclude a finding of obviousness .
In response to Applicants’ assertion that the teachings of the prior art cannot be combined because Lu because (i) Lu already states that “tetraspanins in general can serve as a robust molecular scaffold to display different proteins on exosomes in cultured HEK293 cells” and therefore teaches away from modifying such as scaffold, it is found unpersuasive.
Pursuant to MPEP 2123 (II), “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Lu does teach that tetraspanins in general can serve as a robust molecular scaffold to display different proteins on exosomes in cultured HEK293 cells (see Lu, pg. 4, para[0033]), but such teaching is not a teaching away. Rather, it is a preferred embodiment. Therefore Lu’s teachings are not a reverse teaching that stands in opposition to the claimed invention as Applicants attest. Rather they are preferred embodiments.
In response to Applicants argument that the modification of Lu with Sperlich and Merchant would render Lu’s exosomes unsatisfactory for its intended purpose (see Remarks, filed 11/17/2025, pg. 11), it is found unpersuasive.
Pursuant to MPEP 2143.01(V) states that [i]f a proposed modification would render the prior art invention being modified unsatisfactory for its intended purpose, there may be no suggestion or motivation to make the proposed modification. However, In re Urbanski, 809 F.3d 1237, 1244, 117 USPQ2d 1499, 1504 (Fed. Cir. 2016) (The patent claims were directed to a method of enzymatic hydrolysis of soy fiber to reduce water holding capacity, requiring reacting the soy fiber and enzyme in water for about 60-120 minutes. The claims were rejected over two prior art references, wherein the primary reference taught using a longer reaction time of 5 to 72 hours and the secondary reference taught using a reaction time of 100 to 240 minutes, preferably 120 minutes. The court held that both prior art references "suggest[ed] that hydrolysis time may be adjusted to achieve different fiber properties. Nothing in the prior art teaches that the proposed modification would have resulted in an ‘inoperable’ process or a dietary fiber product with undesirable properties." (emphasis in original)).
It is the Examiner’s understanding that Applicants are suggesting that modifying Lu’s engineered exosomes with Sperlich peptide (i.e., GGKLSK) would forego the benefits taught by Lu (i.e., delivery of bioactive cargo); thereby making Lu’s exosomes unsatisfactory for its intended purposes. However, the modifications to Lu’s exosome discussed above, do not result in an inoperable method of delivering cargo, regardless of the characteristics of exosome’s luminal surface and the scaffold peptide.
With respect to Applicants’ assertion that the claimed composition provides unexpected results (see Remarks filed 11/17/2025, pg. 12-13), it is found unpersuasive.
Pursuant to MPEP 716.02(b)(I), the evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practically significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength “are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.”). See MPEP 716.02(b)(I). In the instant case, Applicants have not provided evidenced that the loading of EVs using the fusion proteins described and claimed procures engineered EVs with significantly higher payload levels. There is no data in the specification that can be traced back to significantly higher payload levels nor that can be compared to other EV for delivering cargo. The only recitation pertaining to a significantly higher payload level is found at pg. 2, para[0004] and reads: “The loading of EV s, e.g.. exosomes, using the fusion proteins described herein produces engineered EVs, e.g, engineered exosomes, with significantly higher payload levels compared to any other genetic engineering method described thus far.” However, such recitation is not sufficient to establish that the instantly claimed invention yields engineered EV’s with significantly higher payload levels nor that the claimed invention is unexpected and unobvious.
With respect to Applicants’ argument that the claimed scaffold proteins having more desired engineered characteristics than fusion to scaffolds known in the art, such as tetraspanins, and are suitable fusion proteins for generating engineered exosomes from several unrelated cell lines derived from different tissues (see Remarks, filed 11/17/2025, pg. 17, second paragraph), it is found unpersuasive.
When reviewing the evidence provided in the specification, it was noted that Example 6, which recites that the results in Example 5 demonstrate that numerous human-derived cells (i.e., HEK293, HT108, K562, MB231, Raji and MSC) naturally express BASP1 (see pg. 120, para[00384]). Pursuant to MPEP 716.02(c)(II), expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). Therefore, eve if the “unexpected result” of (1) having more desired engineered characteristics, and (2) being more suitable fusion proteins for generating engineered exosomes from several unrelated cell lines derived from different tissues, were commensurate in scope with the claimed invention. Since the scope of instant claim 1 encompasses a scaffold protein comprising the N-terminus of BASP1 (i.e., GGKLSK or SEQ ID NO: 203), and since BASP1 is naturally expressed in numerous human-derived cells, the more desired engineered characteristics and the suitability for generating exosomes from different unrelated cell lines and tissues are expected because BASP1 is naturally expressed in different cells and tissues and thus the suitability and desired characteristics are expected and evidence of obviousness.
In response to Applicants request that the provisional double patenting rejections be held in abeyance until all remaining rejections are resolved (see Remarks, filed 08/07/2025, pg. 14, paragraph 4); is acknowledged. As such, the double-patenting rejections are maintained.
Conclusion
No claims are allowed.
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/CLAUDIA ESPINOSA/Patent Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654