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 .
DETAILED ACTION
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Response to Amendments
Applicant’s amendments and response filed Apr. 30, 2026 have been received and entered into the case.
Notice of Change of Examiner
The examiner assigned to the application has changed from Kyle Smith to Emily Cordas.
Status of the Claims
Claims 1-9 and 11-22 are currently pending.
Claims 1, 3-9 and 12 are amended.
Claims 13-15 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claim 10 is cancelled.
Claims 16-22 are new.
Claims 1-9, 11, 12 and 16-22 have been considered on the merits.
Claim Objections
Claim objections are withdrawn due to amendment.
Double Patenting
The nonstatutory double patenting rejections are revised due to amendment.
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.
Claims 1-9, 11, 12, and 16-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 21-29 of copending Application No. 18/165,574 in view of U.S. Patent No. 10139402 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending Application No. 18/165,574 claims:
Claim 1: A method of recovering an extracellular vesicles the method comprising: (1) adding a chelating agent to a sample comprising extracellular vesicles, thereby obtaining a solution comprising the chelating agent and the extracellular vesicles; (2) treating the sample comprising [[an]] extracellular vesicle with a chelating agent in the solution; and (3) separating
Claim 2: The method of claim 1, wherein the chelating agent is at least one selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), glycoletherdiaminetetraacetic acid (EGTA), hydroxyethyl ethylenediaminetriacetic acid (HEDTA), hydroxyethyliminodiacetic acid (HIDA), nitrilotriacetic acid (NTA), oxalic acid, ethylenediaminetetra (methylenephosphonic acid) (EDTMP), and salt thereof, and a mixture thereof.
Claim 3: The method of claim 1, wherein the extracellular vesicle-comprising sample is treated with 1 to 200 mM of the chelating agent.
Claim 5: The method of claim 1, wherein the extracellular vesicle(s) is an exosome.
Claim 6: The method of claim 1, wherein the separating is performed by a precipitation method using an extracellular vesicle membrane-binding substance or an ultracentrifugation method of the sample. Centrifuging of the sample of claim 6 would be readily understood to form a supernatant.
Claim 9: The method of claim 1, wherein the extracellular vesicle-comprising sample is a blood sample, urine, or a breast fluid.
Claim 10: A method of analyzing an extracellular vesicle(s), the method comprising: (1) recovering extracellular vesicles by the method of claim 1, wherein the extracellular vesicles comprise a component to be analyzed
However, copending Application No. 18/165,574 does not recite mixing the sample with a nonionic surfactant simultaneously or separately as part of the recovery/analysis methods, or use of a blood collection vessel as part of the recovery/analysis methods.
Regarding the use of a nonionic surfactant in the method, U.S. Patent No. 10139402B2 discloses, “The problem to be solved by the present invention is to provide a method for separating a vesicle having a lipid bilayer membrane (extracellular vesicle) which the method has excellent removal efficiency of impurity and hardly causes disruption of a vesicle having a lipid bilayer membrane (Column 2, lines 42-46)…Accordingly, the inventors of the present invention conducted intensive studies, and as a result, with regard to a method for separating a vesicle having a lipid bilayer membrane including a complex forming step for forming a complex of a vesicle and a solid phase carrier by bringing a biological sample including the vesicle having the lipid bilayer membrane into contact with the solid phase carrier to which a ligand for recognizing a surface antigen present on a surface of the vesicle is bound and a washing step for washing the complex, the aforementioned problem can be solved if at least any of the complex forming step and the washing step is performed in the presence of a nonionic surfactant” (Column 2, lines 50-62).
U.S. Patent No. 10139402B2 discloses mixing buffer, a nonionic surfactant, and body fluid in a 1.5mL tube (meeting the claim element of “solution” and “blood collection vessel” (Column 23, lines 39-62). Regarding the use of a “blood collection vessel” the instant specification notes, “blood collection vessels are widely used in clinical practice for processing whole blood to prepare blood samples from the viewpoint of convenience, promptness, and the like of processing” (Specification, page 5, para 0012, lines 10-14) …and “As the blood collection vessel, any form can be used, but a tubular form is preferably used” (Specification, page 26, para 0074, lines 8-9). Although U.S. Patent No. 10139402B2 doesn’t explicitly refer to the 1.5mL tube as a “blood collection vessel”, the tube meets the broadest reasonable interpretation of a blood collection vessel.
Regarding the instantly claimed nonionic surfactants, U.S. Patent No. 10139402B2 discloses Pluronic F68 (polyoxyethylene- polyoxypropylene block copolymer, polyoxyethylene alcohol) (Column 20, lines 10-25) as a surfactant in Table 3. The instant specification states, “The method according to [2], wherein the nonionic surfactant having the polyoxyethylene alcohol structure is a polyoxyethylene-polyoxyalkylene block copolymer. “polyoxyethylene- polyoxypropylene” is a species of the genus “polyoxyethylene-polyoxyalkylene”. Therefore, the reference species anticipates the claimed genus, “polyoxyethylene-polyoxyalkylene”. See MPEP § 2131.02 Genus-Species Situations I. A Species Will Anticipate A Claim to a Genus, which states that "A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus.”.
U.S. Patent No. 10139402B2 further discloses the use of Tween 20 as a surfactant in the composition (Column 20, lines 10-25). “Tween 20” is a species of the genus “alcohol ethoxylate”. Therefore, the reference species anticipates the claimed genus, “alcohol ethoxylate”. See MPEP § 2131.02 Genus-Species Situations I. A Species Will Anticipate A Claim to a Genus, which states that "A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus.”.
U.S. Patent No. 10139402B2 further discloses “the HLB (Hydrophile-Lipophile Balance) value of the nonionic surfactant other than the polyalkylene glycol ethylene oxide adduct is preferably 13.1 or more, and more preferably 13.5 or more… Tween 20 has HLB value of 16.7 and Tween 80 has HLB value of 15.0 (Column 20, lines 10-25).
Through routine optimization a person with ordinary skill in the art would be able to use the reference ranges to arrive at the claimed ranges of, “HLB of 18 or more”. 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 adapt the ranges taught by Fujii to arrive at the claimed ranges for use with the same method. See MPEP 2144.05 - Obviousness of Similar and Overlapping Ranges, Amounts, and Proportions - which states that, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
U.S. Patent No. 10139402B2 further discloses that the, “Concentration of the nonionic surfactant is, in terms of final concentration, preferably 0.005% (w/v) or more, more preferably 0.01% (w/v) or more, even more preferably 0.015% (w/v) or more, and particularly preferably 0.02% (w/v) or more, and preferably 10% (w/v) or less” (Column 6, lines 55-59).
Through routine optimization a person with ordinary skill in the art would be able to use the reference ranges to arrive at the claimed ranges of, “0.01 to 10 weight/volume %”. 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 adapt the ranges taught by Fujii to arrive at the claimed ranges to use with the same method. See MPEP 2144.05 - Obviousness of Similar and Overlapping Ranges, Amounts, and Proportions - which states that, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
It would have been prima facie obvious to someone with ordinary skill in the art, before the effective filing date of the claimed invention, to have used a nonionic surfactant in the similar method of Application No. 18/165,574 in view of U.S. Patent No. 10139402B2. This is because a skilled artisan would have been motivated to use a nonionic surfactant in the complex forming, or washing steps, of the method to achieve excellent impurity removal efficiency, and to reduce disruption of the extracellular vesicle.
This is a provisional nonstatutory double patenting rejection.
Claim Rejections - 35 USC § 112
New claim rejections under 35 USC § 112 have been added to address the claim amendments.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 21 and 22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 21 and 22 contain the trademark/trade name TERGITOL®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe non-ionic surfactant and, accordingly, the identification/description is indefinite.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
The claim rejections under 35 USC § 102 are withdrawn due in part to applicant’s arguments and reconsideration of the prior art reference, Fujii.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are revised due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim amendments.
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.
Claims 1-7, 9, 11-12 and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Fujii et al. (U.S. Patent No. 10,139,402 B2) (ref. of record).
Regarding claim 1, the Fujii prior art teaches a “a method for separating (recovering) a vesicle having a lipid bilayer membrane (extracellular vesicle, exosome) (Abstract). Fujii discloses, “According to the present invention, any one of the complex forming step and washing step may be performed in the presence of a nonionic surfactant, or both of the complex forming step and washing step may be performed in the presence of a nonionic surfactant. Furthermore, it is also possible that, before the complex forming step, a composition such as buffer containing a nonionic surfactant is added in advance to a biological sample, and the resultant is used” (Column 7, lines 8-14). Wherein the extracellular vesicle can be separated (recovered) from the biological sample (blood composition, whole blood) (Column 7, lines 55-63), and the components of the blood composition may be treated with an anti-clotting agent such as EDTA (chelating agent) (Column 8, lines 8-11).
Regarding mixing the whole blood with the nonionic surfactant and chelating agent to obtain a mixture solution, see Test Example 12, Detection of Vesicle from body Fluid and Culture Supernatant. The example discloses mixing buffer, a nonionic surfactant, body fluid, and magnetic collection beads bound with anti CD9, anti-CD63, and anti-CD81 (targeting exosomes) in a 1.5mL tube (meeting the claim element of “mixture solution”) (Column 23, lines 39-62). As mentioned previously the whole blood can be treated with EDTA. “EDTA” is a species of the genus “chelating agent”. Therefore, the reference species teaches the claimed genus, “chelating agent”. See MPEP § 2131.02 Genus-Species Situations I. A Species Will Anticipate A Claim to a Genus, which states that "A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus.”.
Following mixing, samples were shaken, washed, and the unreacted solution (mixture solution) was removed by magnetic collecting prior to washing steps (Column 23, lines 63-67). Subsequently samples were prepared for SDS-Page analysis (Column 24, lines 1-25)…Accordingly, by using a particle which bound with a ligand against an antigen…vesicles…can be separated (recovered) from each other and can be detected” (Column 24, lines 33-37).
Regarding separating the extracellular vesicle from the mixture solution, the instant specification states, “The separation in a process (2) can be performed
in any manner. For example, the separation may be performed by any of the following (A) to (C): (A) collection of supernatant from the mixture solution; (B) use of a substance capable of binding to a surface marker of the extracellular vesicle in the mixture solution; or (C) collection of supernatant from the mixture solution and use of the substance capable of binding to the surface marker of the extracellular vesicle in the supernatant” (Page 20, para 0058, lines 13-22).
Since Fujii teaches alternative body fluids including whole blood (Column 7, lines 55-63) and where the fluid is treated with EDTA (Column 8, lines 8-11), it would have been obvious to one of ordinary skill in the art to substitute the body fluid of Test Example 12 with whole blood treated with EDTA. One of ordinary skill in the art would have been motivated to make such a modification for the benefit of recovering extracellular vesicles from addition sources and since Fujii teaches the method using alternative body fluids including whole blood. Additionally, one of ordinary skill in the art would have had a reasonable expectation in making such a modification to the method of Fujii for these same reasons.
Regarding claim 2, Fujii discloses Pluronic F68 (polyoxyethylene- polyoxypropylene block copolymer) (Column 20, lines 10-25) as a surfactant in Table 3. The instant specification states, “The method according to [2], wherein the nonionic surfactant having the polyoxyethylene alcohol structure is a polyoxyethylene-polyoxyalkylene block copolymer. “polyoxyethylene- polyoxypropylene” is a species of the genus “polyoxyethylene-polyoxyalkylene”. Therefore, the reference species anticipates the claimed genus, “polyoxyethylene-polyoxyalkylene”. See MPEP § 2131.02 Genus-Species Situations I. A Species Will Anticipate A Claim to a Genus, which states that "A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus.”.
Regarding claim 3, Fujii discloses the use of Tween 20 as a surfactant in the composition (Column 20, lines 10-25). “Tween 20” is a species of the genus “alcohol ethoxylate”. Therefore, the reference species anticipates the claimed genus, “alcohol ethoxylate”. See MPEP § 2131.02 Genus-Species Situations I. A Species Will Anticipate A Claim to a Genus, which states that "A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus.”.
Regarding claim 4, as discussed in the rejection of claim 2, the prior art species polyoxyethylene- polyoxypropylene anticipates the claimed genus polyoxyethylene- polyoxyalkylene. Therefore, the disclosure of Pluronic F68 in the prior art meets the instant claim limitation of polyoxyethylene-polyoxyalkylene block copolymer.
Regarding claim 5, Fujii discloses, “the HLB (Hydrophile-Lipophile Balance) value of the nonionic surfactant other than the polyalkylene glycol ethylene oxide adduct is preferably 13.1 or more, and more preferably 13.5 or more… Tween 20 has HLB value of 16.7 and Tween 80 has HLB value of 15.0” (Column 20, lines 10-25).
Through routine optimization a person with ordinary skill in the art would be able to use the reference ranges to arrive at the claimed range of, “HLB of 18 or more”. 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 adapt the ranges taught by Fujii to arrive at the claimed ranges for use with the similar method. See MPEP 2144.05 - Obviousness of Similar and Overlapping Ranges, Amounts, and Proportions - which states that, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
Regarding claim 6, Fujii discloses that the, “Concentration of the nonionic surfactant is, in terms of final concentration, preferably 0.005% (w/v) or more, more preferably 0.01% (w/v) or more, even more preferably 0.015% (w/v) or more, and particularly preferably 0.02% (w/v) or more, and preferably 10% (w/v) or less” (Column 6, lines 55-59).
Through routine optimization a person with ordinary skill in the art would be able to use the reference ranges to arrive at the claimed ranges of, “0.01 to 10 weight/volume %”. 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 adapt the ranges taught by Fujii to arrive at the claimed ranges to use with the similar method. See MPEP 2144.05 - Obviousness of Similar and Overlapping Ranges, Amounts, and Proportions - which states that, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
Regarding claim 7, as mentioned in the discussion of claim 1 above, Fujii discloses the use of EDTA (ethylenediaminetetraacetic acid) in the mixture.
Regarding claim 9, the instant specification notes, “blood collection vessels are widely used in clinical practice for processing whole blood to prepare blood samples from the viewpoint of convenience, promptness, and the like of processing” (Specification, page 5, para 0012, lines 10-14) …and “As the blood collection vessel, any form can be used, but a tubular form is preferably used” (Specification, page 26, para 0074, lines 8-9). As discussed in claim 1, Fujii discloses the components mixed in a 1.5mL tube. Although Fujii doesn’t explicitly refer to the 1.5mL tube as a “blood collection vessel”, the tube meets the broadest reasonable interpretation of a blood collection vessel.
Regarding claim 11, Fujii discloses the method relates to a method for separating a vesicle having a lipid bilayer such as an exosome (Column 1, lines 10-21).
Regarding claim 12, Regarding a method of analyzing an extracellular vesicle the instant specification states, “The processes (1) and (2) in the analysis method of the present invention can be performed in the same way as the processes (1) and (2) in the recovery method of the present invention. [0068] In the process (3), the extracellular vesicle can be analyzed after the separation of the extracellular vesicle or simultaneously with the separation of the extracellular vesicle. Examples of an analyte in the analysis of the extracellular vesicle include components contained in the extracellular vesicle (e.g., components contained inside the extracellular vesicle, membrane components of the extracellular vesicle, components present on the membrane surface of the extracellular vesicle) and extracellular vesicle itself (particle) (Specification, Page 24, para 0069, lines 23-27).
Fujii provides several examples of the use of the method disclosed in the discussion of claim 1 for the analysis of a sample following practice of the separation method, including detection of nucleic acid, microRNA, and protein in the extracellular vesicle (Columns 21-23).
Regarding claim 16 and mixing the whole blood with both the nonionic surfactant and chelating agent simultaneously to obtain a mixture solution, see Test Example 12, Detection of Vesicle from body Fluid and Culture Supernatant. The example discloses mixing buffer, a nonionic surfactant, body fluid, and magnetic collection beads bound with anti CD9, anti-CD63, and anti-CD81 (targeting exosomes) in a 1.5mL tube (meeting the claim element of “mixture solution”) (Column 23, lines 39-62). As mentioned previously the whole blood can be treated with EDTA. “EDTA” is a species of the genus “chelating agent”. Even though Fujii does not explicitly teach the mixing is performed simultaneously, all components would be present when whole blood treated with EDTA is used.
Regarding claims 17-19 and separating is performed by forming a supernatant from the mixture solution, wherein the supernatant comprises the extracellular vesicle, the nonionic surfactant and the chelating agent; and collecting the supernatant, see Background Art (column 2) in combination with Test Example 12, Detection of Vesicle from body Fluid and Culture Supernatant. The Background Art discloses centrifuging a plasma sample which would form a supernatant and reacting the supernatant with an antibody against transmembrane proteins expressed on exosomes (isolating the extracellular vesicle from the supernatant with a substance capable of binding to the surface marker of the extracellular vesicle). Test Example 12 discloses mixing buffer, a nonionic surfactant, body fluid, and magnetic collection beads bound with anti CD9, anti-CD63, and anti-CD81 (targeting exosomes) in a 1.5mL tube (meeting the claim element of “mixture solution”) (Column 23, lines 39-62). As mentioned previously the whole blood can be treated with EDTA. Since Fujii teaches an alternative method of isolating the exosomes using antibodies (Background Art), alternative body fluids including whole blood (Column 7, lines 55-63) and where the fluid is treated with EDTA (Column 8, lines 8-11), it would have been obvious to one of ordinary skill in the art to substitute the method of isolating the extracellular vesicle of Test Example 12 with a method where the extracellular vesicle are isolated from the supernatant obtained by centrifuging the mixture solution with a substance capable of binding to the surface marker of the extracellular body fluid and where the body fluid is whole blood treated with EDTA. One of ordinary skill in the art would have been motivated to make such a modification for the benefit of recovering extracellular vesicles from addition sources and using known techniques and since Fujii teaches alternative methods of isolating extracellular vesicles and methods using alternative body fluids including whole blood. Additionally, one of ordinary skill in the art would have had a reasonable expectation in making such a modification to the method of Fujii for these same reasons.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 8 is rejected under 35 U.S.C. 103(a) as being unpatentable over Fujii (as applied to claims 1-7, 9, 11-12, and 16-19 above), and further in view of Tatsutoshi (Ep Application No. 17860942.6)(ref. of record).
The teachings of Fujii can be found in the previous rejection above.
Fujii does not teach the method where the concentration of chelating agent in the mixture solution is from 10 to 1000 mM as recited in claim 8.
However, Tatsutoshi teaches a similar method of recovering extracellular vesicles comprising treating the extracellular vesicle with 1 to 200 mM of the chelating agent (Page 2, para 0008, lines 45-58).
Through routine optimization a person with ordinary skill in the art would be able to use the reference ranges to arrive at the claimed ranges of, “10 mM to 1000 mM”. 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 adapt the ranges taught by Fujii in view of Tatsutoshi to arrive at the claimed ranges to use with the similar method. See MPEP 2144.05 - Obviousness of Similar and Overlapping Ranges, Amounts, and Proportions - which states that, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. Therefore, the instant claim is obvious in view of the prior art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 20-22 are rejected under 35 U.S.C. 103(a) as being unpatentable over Fujii (as applied to claims 1-7, 9, 11-12, and 16-19 above), and further in view of Kim et al. (US 2022/0283149 A1, priority to Aug. 6, 2019).
The teachings of Fujii can be found in the previous rejection above.
Fujii does not teach the method where the alcohol ethoxylate is a branched-chain alcohol ethoxylate represented by Formula (1) as recited in claim 20, where the branched-chain alcohol ethoxylate of Formula (1) is a TERGITOL® series compound as recited in claim 21, or where the branched-chain alcohol ethoxylate of Formula (1) is TERGITOL® 15-S-40 as recited in claim 22.
However, Kim reports neutral surfactants include TWEEN-20, β-octyl-glucoside, octyl-β-thio-glucopyranoside, Triton X-100, Triton X-114, NP-40, Brij-35, Brij-58, Tween-80, Pluronic F-68, Pluronic F-127, Deoxy Big CHAP, CHAPS, CHES, and nonylphenoxylpolyethoxylethanol (Tergitol type NP-40) (0081).
At the time of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of Fujii in such a way that the non-ionic surfactant is a Tergitol type NP-40 represented by Formula (1) for the purpose being able isolating extracellular vesicles. Furthermore, it would have been obvious to one skilled in the art to have further modified Fujii such that non-ionic surfactant is a Tergitol type NP-40 represented by Formula (1), since this is a known ionic surfactant as taught by Kim. Such a modification merely involves the substitution of one known type of non-ionic surfactant for another in a method of isolating extracellular vesicles. Although, Kim does not teach the specific Tergitol 15-S-40, Kim teaches any Tergitol type NP-40. Accordingly, it would have been obvious to use Tergitol 15-S-40.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Apr. 30, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 102, Applicant argues that there is no prior art attempt to recover extracellular vesicles (EVs) from whole blood and Fujii does not have any working examples of collecting EVs from whole blood (Remarks pg. 7 para. 3). Although, the rejections under 35 U.S.C. § 102 have been withdrawn, these arguments were not found to be persuasive, since Fujii clearly teaches recovering exosomes from whole blood (Column 7 lines 55-63). Additionally, Fujii teaches the claimed method of recovering an extracellular vesicle by mixing whole blood with a nonionic surfactant and a chelating agent to obtain a mixture solution and separating the extracellular vesicles as explained in the rejections and proof of efficacy or working examples are not needed for a prior art reference to make obvious the claimed invention. It is noted that prior art is presumed to be operable or enabling. Please see MPEP 2121 which states; “When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability”.
Applicant argues that whole blood is very different from plasma and serum, must be collected in a blood collection vessel with an anticoagulant and contains different components compared to plasma and serum (Remarks pg. 7 para. 4 to pg. 8 para. 3). Applicant argues that the use of surfactants in processing whole blood for clinical purposes is considered undesirable and teaches away from using surfactants, since surfactants disrupt lipid bilayers and cause hemolysis (Remarks pg. 8-9 bridging para.). Applicant argues that in contrast to the common knowledge at the time, the present inventors found that by applying a nonionic surfactant and a chelating agent to whole blood it is possible to prepare a blood sample for EV analysis (Remarks pg. 9 para. 2). However, these arguments were not found to be persuasive, since Fujii makes obvious the claimed invention and teaches the use of non-ionic surfactant in a method of recovering extracellular vesicles from body fluids. Additionally, Fujii teaches that the body fluid may be whole blood treated with EDTA.
Applicant argues that the claimed invention significantly improves the recovery of EVs from whole blood as demonstrated in Example 4 which shows the combination of a chelating agent and nonionic surfactant synergistically enhanced EV recovery. Although the data shows when increasing concentrations of EGTA and Tergitol 15-S-40 are added to whole blood there is an increase in EV (extracellular vesicle recovery), the data is not commensurate in scope with the claim invention. The claimed method is broader than the method for generating the data in the example. Specifically, the method used in Example 4 uses a particular chelating agent (EDTA) and particular non-ionic surfactant (Tergitol 15-S-40). It is unclear if the same effects would be achieved under different conditions.
Applicant argues that Example 5 shows that the effects of the chelating agent and the surfactant are directed to the whole blood and not the immunological reaction in the CD9 assay system (Remarks pg. 10 para. 3). However, these arguments fail to persuade because, Fujii makes obvious the claimed invention and teaches the use of non-ionic surfactant in a method of recovering extracellular vesicles from body fluids. Thus, the claimed function must be inherent to the method of Fujii. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art's functioning, does not render the old composition patentably new. Thus the claiming of a new use, functions or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. (MPEP 2112)
Applicant argues that Example 6 further demonstrates the synergistic effects of the combination of a chelating agent and nonionic surfactant synergistically enhanced EV recovery with additional nonionic surfactants (Remarks pg. 10 last para. to pg. 12 para. 1). Although the data shows when EGTA and one of the non-ionic surfactants of Tergitol, Pluronic F68, Pluronic F108, and Pluronic F127 are added to whole blood there is an increase in EV (extracellular vesicle recovery), the data is not commensurate in scope with the claim invention. The claimed method is broader than the method for generating the data in the example. Specifically, the method used in Example 6 uses a particular chelating agent (EGTA) and particular non-ionic surfactant (Tergitol, Pluronic F68, Pluronic F108, and Pluronic F127). It is unclear if the same effects would be achieved under different conditions.
Applicant argues that Fujii does not teach the alcohol ethoxylate of new claims 20-22 and only teaches Tween 20 (Remarks pg. 12 para. 4-5). The Applicant’s amendments including new claims 20-22 necessitated new rejections. Applicant’s arguments are drawn to Fujii failing to teach this new limitation. However, the new claims are addressed in the new rejections.
Applicant argues that Fujii teaches that the nonionic surfactant is required during and after the reaction between the EV and the ligand (Remarks pg. 13 para. 1). This argument was not found to be persuasive, since Fujii teaches recovering exosomes from whole blood (Column 7 lines 55-63). Additionally, Fujii teaches or makes obvious the claimed method of recovering an extracellular vesicle by mixing whole blood with a nonionic surfactant and a chelating agent to obtain a mixture solution and separating the extracellular vesicles as explained in the rejections. The described requirement of the nonionic surfactant for during and after the reaction between the EV and the ligand of Fujii does change that Fujii teaches or makes obvious the claimed method.
Applicant argues that Fujii does not have any working examples of collecting EVs from whole blood (Remarks pg. 13 para. 2). Similarly, Applicant argues that the Examiner’s allegations about Test Example 12 of Fujii are incorrect and that the example describes mixing magnetic particles, a nonionic surfactant and heparin blood plasma and not mixing whole blood with the nonionic surfactant and chelating agent (Remarks pg. 13 last para. to pg. 15 para. 3). These arguments were found to persuasive with respect to the rejections under 35 U.S.C. § 102 and the rejections have been withdrawn. However, these arguments were not found to be persuasive with respect to the rejections under 35 U.S.C. § 103, since Fujii clearly teaches recovering exosomes from whole blood (Column 7 lines 55-63). Additionally, Fujii teaches or makes obvious the claimed method of recovering an extracellular vesicle by mixing whole blood with a nonionic surfactant and a chelating agent to obtain a mixture solution and separating the extracellular vesicles as explained in the rejections.
Applicant argues that Test Example 12 teaches away from the claimed invention in view of the common knowledge in the art at the time of filing, since there is no motivation to add an anti-clotting agent such as a chelating agent to heparin blood plasma, since plasma does not coagulate and a person skilled in the art would not further treat blood samples with additional agents (Remarks pg. 15 last para. to pg. 16 para. 3). However, this argument was not found to be persuasive, since Fujii teaches adding EDTA to whole blood (column 8, lines 8-11) and it is maintained that it would have been obvious to one of ordinary skill in the art to substitute the body fluids in Test Example 12 with whole blood as explained in the rejections under 35 U.S.C. § 103. Furthermore, Fujii does not explicitly state that whole blood treated with EDTA cannot be used in the method.
Applicant argues that Fujii does not teach a buffer containing a nonionic surfactant is added in advance to the biological sample; EVs are not separated from whole blood in the Examples; the components of the blood composition is not treated with a chelating agent such as EDTA in the Examples; and the whole blood is not mixed with the nonionic surfactant and chelating agent in the Examples (Remarks pg. 16 last para. to pg. 17 para. 3). Applicant further argues that Fujii does not teach the specific combination of treatments agents, a specific chelating agent and a specific surfactant (non-ionic) for the specific application of recovering EVs from whole blood (Remarks pg. 17 para. 4). Applicant argues that the claimed invention has significant effects that cannot be predicted based on Fujii, since Fujii does not teach recovery of EVs from whole blood, the use of a chelating agent or the treatment of EVs with a chelating agent and nonionic surfactant before the complex forming step (Remarks pg. 17-18 bridging para.). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a nonionic surfactant is added in advance to the biological sample or before the complex forming step) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, these arguments were not found to be persuasive with respect to the rejections under 35 U.S.C. § 103, since Fujii clearly teaches recovering exosomes from whole blood (Column 7 lines 55-63). Additionally, Fujii teaches or makes obvious the claimed method of recovering an extracellular vesicle by mixing whole blood with a nonionic surfactant and a chelating agent to obtain a mixture solution and separating the extracellular vesicles as explained in the current rejections.
Applicant argues that the improvement in the recovery of EVs from whole blood by mixing whole blood with a nonionic surfactant and chelating agent is different from the teaching in Fujii that nonionic surfactant is required for suppressing non-specific adsorption in an immunological reaction (Remarks pg. 18 para. 2). However, these arguments fail to persuade because, Fujii makes obvious the claimed invention and teaches the use of non-ionic surfactant in a method of recovering extracellular vesicles from body fluids. Thus, the claimed function must be inherent to the method of Fujii. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art's functioning, does not render the old composition patentably new. Thus the claiming of a new use, functions or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. (MPEP 2112)
Applicant further argues that Fujii does not teach any of the new claims (Remarks pg. 18 para. 3 to pg. 19 para. 1). The Applicant’s amendments including new claims 16-22 necessitated new rejections. Applicant’s arguments are drawn to Fujii failing to teach this new limitation. However, the new claims addressed in the new rejections.
With respect to the double patenting rejections, Applicant argues that the claims of US Appl. No. 18/165574 do not recites mixing the sample with a nonionic surfactant and Fujii, as explained in the arguments with respect to the prior art rejections does not teach the missing elements (Remarks pg. 19 para. 6 to pg. 20 para. 1). However, this argument was not found to be persuasive, since the arguments with respect to the rejections over Fujii were not found to be persuasive as explained above.
Conclusion
No claims are 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.
Examiner Contact Information
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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