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 .
Status of claims
Claims 1, 2, 4, 6-9 and 12-23 as amended on 10/20/2025 are pending.
Claims 20-23 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/12/2025.
Claims 1, 2, 4, 6-9 and 12-19 as amended on 10/20/2025 are under examination in the instant office action.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 4, 6-9, 12, 16 and 19 as amended remain or are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by WO 2019/039179 (Kuroda et al) as evidenced by “MoBiTech” product description (webpage https://www.mobitec.com/magtivio/#manufacturer-products retrieved on 2/11/2026, pages 1-7).
WO 2019/039179 (Kuroda et al) discloses a method for microvesicles or exosomes from a biological sample, wherein the method comprises steps (see English abstract and figure 8 on the face of printed document):
(a) adding an adsorbent sphere or beads to the biological sample containing the exosomes therein;
(b) keeping the adsorbent beads in the biological sample to form an adsorbent conjugate composed of the adsorbent beads and the exosomes captured thereon (step GG on the figure 8);
(c) isolating the adsorbent conjugate from the biological sample;
(d) washing the isolated adsorbent conjugate using a first reagent (step HH on figure 8); and
(e) eluting the exosomes from the washed adsorbent conjugate using a second reagent (step II on figure 8),
wherein the adsorbent beads are “polylysine-silica magnetic beads” (see description of item EE on figure 8 on a front page of WO 2019/039179 (Kuroda et al) that include a support (magnetic beads) and one or more polyvalent cations such as polylysine bound to magnetic beads, thus, disposed on a surface of the support, to provide for binding of exosome.
Now with regard to the presently claimed support structure:
The cited document WO 2019/039179 (Kuroda et al) clearly teaches the use of “polylysine-silica magnetic beads” as magnetic beads. Polylysine is deposited on “silica magnetic” beads (see translation pages 18-19). The support itself which is “silica-magnetic” beads clearly contains 2 different materials including magnetic material and silica. One of skill in the art would clearly recognize and/or acknowledge that magnetic material must be a metal and not a silica. Thus, the support of contains magnetic metal as a core and silica as shell; or, vice versa as allowed by the claims. In fact, the silica magnetic beads of WO 2019/039179 (Kuroda et al) are “MoBiTec” product (see translation page 18, lines 18-20). The MoBiTec beads accordingly to product description are “ferrimagnetic”, meaning comprise metal Fe, Ni, etc; and they are “silica-enclosed”, meaning silica is a shell.
Thus, the cited document WO 2019/039179 (Kuroda et al) anticipates claim 1.
As applied to claim 2: the biological samples comprising exosomes include blood, plasma, serum, urine, saliva, cerebrospinal fluid (see machine translation page 1 par. 3 at section “description”; see machine translation page 5, par. 4).
As applied to claims 4 and 9: the polyvalent cation includes polylysine (see English abstract and figure 8; see machine translation page 6).
As applied to claims 6 and 7: the support materials include silica and/or latex (page 7, line 6), thereby, some porous particle and/or mesh with irregularities on the surface within the broadest reasonable meaning of the claims.
As applied to claim 8: in the cited method the support is clearly magnetic bead (entire document); and the magnetic beads are widely and commonly used by those skill in the art (page 7, par. 1), thus, inherently made with most common magnetic metals at least iron (Fe), nickel (Ni), cobalt (Co).
As applied to claims 12 and 16: in the cited method the adsorbent conjugate comprising magnetic materials is isolated by magnetic isolation by magnetic force or using magnet (figure 8). The cited method comprises 2 consecutive steps including washing conjugate under conditions that complex does not dissociate (see figure 8, see machine translation page 13, par. 5-6) followed using a dissociation solution to isolate absorbent magnetic bead from exosomes (figure 8; machine translation page 23); thereby practicing “first auxiliary isolation” and “second auxiliary isolation” within the meaning of the claims.
As applied to claim 19: the cited document acknowledges that exosomes have average diameter 20-120 nm (Page 1); and in the cited method the polyvalent cation is poly-L-lysine polymer with positive charge (pages 5-6).
Thus, the cited document WO 2019/039179 (Kuroda et al) anticipates the claimed invention.
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.
Claims 1, 2, 4, 6-9, 12 and 15-19 as amended remain or are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/039179 (Kuroda et al) as evidenced by “MoBiTech” product description, WO 2017/178472 (Deregibus et al) and US 6,743,585 (Dellinger e al).
WO 2019/039179 (Kuroda et al) discloses a method for microvesicles or exosomes from a biological sample, wherein the method comprises steps (see English abstract and figure 8 on the face of printed document):
(a) adding an adsorbent sphere or beads to the biological sample containing the exosomes therein;
(b) keeping the adsorbent beads in the biological sample to form an adsorbent conjugate composed of the adsorbent beads and the exosomes captured thereon (step GG on the figure 8);
(c) isolating the adsorbent conjugate from the biological sample;
(d) washing the isolated adsorbent conjugate using a first reagent ( step HH on figure 8); and
(e) eluting the exosomes from the washed adsorbent conjugate using a second reagent (step II on figure 8).
In particular, in the method of the cited WO 2019/039179 (Kuroda et al) the adsorbent beads includes a support that is made from silica and magnetic material, wherein the adsorbent silica magnetic beads and the polyvalent cation such as positively charged polylysine is disposed on a surface of the adsorbent beads. The silica magnetic beads of WO 2019/039179 (Kuroda et al) are “MoBiTec” product (see translation page 18, lines 18-20). The MoBiTec beads accordingly to product description are “ferrimagnetic”, meaning comprise metal Fe, Ni, etc; and they are “silica-enclosed”, meaning silica is a shell.
The cited WO 2019/039179 (Kuroda et al) is silent with regard to other various support materials for incorporation into beads.
However, WO 2017/178472 (Deregibus et al) teaches the use of other or alternative positively charged peptide such as protamine for interacting with negatively charged exosomes (paragraph bridging pages 3 and 4) and other or alternative support/core materials for absorbent beads such as hydrogel, agarose, polyethylene glycol (page 5, par. 4). In addition, the cited US 6,743,585 (Dellinger e al) teaches that support materials for binding moieties of conjugates can be of different shapes, can be porous or non-porous, can be made from various materials including silica, polyacrylates, polystyrene, polyethylene, ceramics, metals (col. 8, lines 43-65).
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to use various alternative materials for providing absorbent beads with a reasonable expectation of success in isolating exosomes because claimed materials have been known and used in the prior art for isolation of exosomes by forming absorbent bead conjugates. Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
Further, the cited WO 2019/039179 (Kuroda et al) also recognizes that exosome capturing and separations can be performed by using capturing filters with pore size in the range 20-200 nm (page 2, lines 1-2) as encompassed the claim 15.
Furthermore, the cited WO 2019/039179 (Kuroda et al) clearly recognizes interaction or binding between positively charged polycationic substances lysine/polylysine and negatively charged exosomes (Page 5, last par.) But it is silent about zeta potential. However, WO 2017/178472 (Deregibus et al) discloses that zeta potential of polycationic substances is 2-20 mV (Page 5, lines 1-2) which overlap the range as encompassed by claim 18.
With regard to claims 17 it is noted that although the cited document WO 2019/039179 (Kuroda et al) does not teach the use 800 nm filter for pretreatment of biological sample, it clearly discloses the size of exosomes being 20-120 nm (page 1 of machine translation). Thus, it is obvious the use 800 nm filter for pretreatment of biological sample (such as blood, for example) as to remove large cells or large blood cells in the method of WO 2019/039179 (Kuroda et al) to provide for exosome pre-concentrated sample.
Thus, the claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Claims 1, 2, 4, 6-9 and 12-19 as amended are/remain rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/039179 (Kuroda et al) as evidenced by “MoBiTech” product description, WO 2017/178472 (Deregibus et al) and US 6,743,585 (Dellinger e al) as applied to claims 1, 2, 4, 6-9, 12 and 15-19 above, and further in view of Sawyer et al (“The dissociation of proteins by chaotropic salts”. The Journal of Biological Chemistry. 1973, vol. 248, No. 24, pages 8429-8433).
WO 2019/039179 (Kuroda et al) discloses a method for microvesicles or exosomes from a biological sample, wherein the method comprises steps (see English abstract and figure 8 on the face of printed document):
(a) adding an adsorbent sphere or beads to the biological sample containing the exosomes therein;
(b) keeping the adsorbent beads in the biological sample to form an adsorbent conjugate composed of the adsorbent beads and the exosomes captured thereon (step GG on the figure 8);
(c) isolating the adsorbent conjugate from the biological sample;
(d) washing the isolated adsorbent conjugate using a first reagent ( step HH on figure 8); and
(e) eluting the exosomes from the washed adsorbent conjugate using a second reagent (step II on figure 8).
In particular, WO 2019/039179 (Kuroda et al) clearly recognizes that intact and pure exosomes are obtained and separated from absorbent conjugates by 2 consecutive steps including washing conjugate under conditions that complex does not dissociate by using a buffer as a first reagent (see figure 8, see machine translation page 13, par. 5-6) followed by the use of a second reagent or a dissociation solution to dissociate and to isolate absorbent magnetic bead from exosomes (figure 8; machine translation page 23); wherein the second reagent or dissociation solution contains chloride ion Cl - or KCl or MgCl at a concertation 0.5 M (see figure 8, see machine translation page 21 last par. 21; page 22 par. 2-3) as encompassed by claim 14. The separation or dissolution of absorbent conjugate is practiced via mixing by centrifugation at 500-4000g (page 13, par. 2).
With regard to a first reagent for washing the adsorbent conjugate the cited WO 2019/039179 (Kuroda et al) discloses the use of a buffer or PBS buffer as a first reagent (see figure 8, see machine translation page 13, par. 5-6). But it does not recognize effect of chaotropic salts for dissociation of contaminating proteins. Nevertheless, WO 2019/039179 (Kuroda et al) recognizes a problem of a large amount of contaminating proteins when centrifugation is used for isolation of exosomes (page 2, par. 5).
However, Sawyer teaches the use of chaotropic salts for dissociation of contaminating proteins including the use of acetate buffer (figures 1, 3) for protein washing and dissociation of proteins.
Therefore, it would have been obvious to one having ordinary skill in the art at the time the claimed invention was filed to substitute acetate buffer of Sawyer for PBS buffer in the method of WO 2019/039179 (Kuroda et al) with a reasonable expectation of success in isolating pure exosomes because WO 2019/039179 (Kuroda et al) recognizes presence and problems of contaminating proteins in the process for isolation of exosomes and because acetate or acetate buffer has been knonw and used for dissociating proteins as adequately demonstrated by Sawyer. Thus, one of skill in the art would have been motivated to use acetate or acetate buffer suggested by Sawyer for dissociation and/or removing contaminating proteins present together with exosomes in biological samples.
Thus, the claimed invention as a whole was clearly prima facie obvious, especially in the absence of evidence to the contrary.
Thus, the claimed subject matter fails to patentably distinguish over the state art as represented be the cited references. Therefore, the claims are properly rejected under 35 USC § 103.
Response to Arguments
Applicant's arguments filed on 10/20/2025 have been fully considered but they are not persuasive.
With regard to claim rejection under 35 U.S.C. 102 (a) (1) as being anticipated by WO 2019/039179 (Kuroda et al) Applicants argue that the cited reference does not teach the same structure of the support in the absorbent spheres as presently claimed in the method for macrovesicle isolation.
This argument is not found persuasive.
The cited document WO 2019/039179 (Kuroda et al) clearly teaches the use of “polylysine-silica magnetic beads” as magnetic beads in the method for macrovesicle isolation. Polylysine is deposited on “silica magnetic” beads (see translation pages 18-19). The support itself which is “silica-magnetic” beads clearly contains 2 different materials including magnetic material and silica. One of skill in the art would clearly recognize and/or acknowledge that magnetic material must be a metal and not a silica. Thus, the support of contains magnetic metal as a core and silica as shell; or, vice versa as allowed by the claims. In fact, the silica magnetic beads of WO 2019/039179 (Kuroda et al) are “MoBiTec” product (see translation page 18, lines 18-20). The MoBiTec beads accordingly to product description are “ferrimagnetic”, meaning comprise metal Fe, Ni, etc; and they are “silica-enclosed”, meaning silica is a shell.
Thus, the cited document WO 2019/039179 (Kuroda et al) anticipates the claimed method.
With regard to claim rejection under 35 U.S.C. 103 Applicants’ arguments is the same that the primary refences does not teach or suggest the structure of the absorbent beads and that the secondary references do not teach/suggest this deficiency.
This argument is not found persuasive. The cited document WO 2019/039179 (Kuroda et al) does teach the use of “polylysine-silica magnetic beads” of the same structure and materials within the meaning of the claims as explained above and also in view of evidentiary reference to the description of the same or similar “MoBiTec” product. The secondary references are relied upon for suggestion of the various alternative and/or additional materials. Thus, the cited references are in the same field of endeavor and they seek to solve the same problems as the instant application and claims, and one of skill in the art is free to select components available in the prior art, In re Winslow, 151 USPQ 48 (CCPA, 1966).
No claims are allowed.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Vera Afremova
February 12, 2026
/VERA AFREMOVA/ Primary Examiner, Art Unit 1653