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 .
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 (i.e., changing from AIA to pre-AIA ) 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.
Priority
The present application is filed as a Continuation of 16/227,436, filed 12/20/2018 (abandoned), which is filed as a Continuation-in-part of 14/419,665, filed 02/05/2015 (US Patent No. 12,276,658). Application 14/419,665 was filed as a proper National Stage (371) entry of PCT Application No. PCT/PCT/CA2013/000733, filed 08/22/2013 which claims benefit under 35 U.S.C. 119(e) to provisional application Nos. 61/781,651, filed 03/14/2013 and 61/692,422, filed 08/23/2012.
Information Disclosure Statement
The information disclosure statement filed 12/24/2026 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
Specifically, there does not appear to be a copy of each of the lined through references on the IDS 12/24/2026 present in the instant application, or in application nos. 16/227/436 or 14/419,665.
Claim Rejections - 35 USC § 112
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 1-11 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.
The preamble of claim 1 recites separating exosomes and/or microvesicles, the claim reciting a step of preparing the sample by “removing cells and cellular debris relatively larger than the exosomes and/or microvesicles”; however, this language is indefinite claim language because of the relative term “relatively”. The term “relatively” is not defined by the claim, the specification does not the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. See MPEP 2173.05(b). Notably, microvesicles/exosomes are/can be considered to be cellular debris themselves, in so far as they are derived from/parts released from, whole cells, and further the terminology “relatively larger” is also indefinite as it fails question as to what components would and would not be considered “relatively” larger. There is no clear distinction between what would be considered debris and what would not.
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.
Claim(s) 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Lewis et al., US PG Pub No. 2012/0058480A1 (IDS entered 12/24/2024) in view of Dowd et al., WO2009/127045A1 (IDS entered 12/24/2024), Skold, US PG Pub No. 2002/0000398 A1 (IDS entered 12/24/2024), Anastase et al., Affinity Chromatography of human anti-dextran antibodies Isolation of two distinct populations, Journal of Chromatography B, 686, (1996), p. 141-150 (IDS entered 12/24/2024) and Lim, WO2009/105044A1 (IDS entered 12/24/2024), and as evidenced by Greenfeder et al., US PG Pub No. 2003/0194404A1 (IDS entered 12/24/2024).
Lewis teach fetal microparticle enrichment/detection in a maternal sample such as whole blood, plasma, serum, urine or mucus (microparticles of Lewis are subcellular microparticles, namely membrane bound bodies arising from fetal tissue, trophoblasts, and placenta tissue, see para [0010], which membrane bound bodies read on the claimed exosomes and microvesicles, see as exosomes and microvesicles are considered membrane bound bodies, namely particles that are derived from cells). The samples of Lewis are samples comprising cells, cellular debris, exosomes and microvesicles (see for example, the originally filed specification similarly is referring to samples that are whole blood samples, e.g., para [0058] of the originally filed specification). Lewis teach methods comprising binding the target to a label (magnetic particle) through a linking system comprising a first polymer (dextran) and a ligand that binds the first polymer (anti-dextran antibody) (see Lewis, for example, at paras [0010], [0011], [0032]-[0035] and [0140], methods comprising the use of a tetrameric antibody linking system to link dextran coated particle with antigen on the target microparticle).
Lewis does teach, prior to enrichment (separation) of the fetal microparticles, a first step of removing residual cells, see specifically Lewis does teach a first step enrichment by centrifugation (see para [0126], centrifugation to separate from whole blood, plasma then centrifuged at 1,600xg to remove residual cells, finally cell free plasma subjected to a further 2 step centrifugation to obtain platelet free plasma (PFP), namely centrifugation at between 1200-1500xg for 10-20 minutes, followed by 10000-13000xg for 30 minutes, supernatant contains microparticles/bodies (platelet free), then pelleted and resuspended). As such, Lewis does address the claimed step of “preparing the sample by removing cells and cellular debris”, because it would be the case that Lewis’ step of centrifugation to remove cells (and platelets) would also result in removal of other debris, thereby providing a purified pellet containing the targeted microparticles of Lewis. Also notably, the “preparing step” as taught by Lewis (namely, the step of centrifugation, as taught by Lewis) is consistent with the step indicated by Applicant’s own originally filed disclosure as the step claimed for purification and the removal of cells and other cellular debris (see page 74, centrifuging sample to remove cells, and other larger debris). This step as taught by Lewis (the centrifugation) is the same as that which applicant discloses in their specification as “purifying exosomes and microvesicles”, namely is purifying by centrifugation to remove that which is not the targeted microparticles, and as such, Lewis addresses this limitation because it is the case that Lewis’s centrifugation would similarly result in removal of cells and cellular debris larger than that exosomes/microvesicles.
Lewis et al. differs from the claimed invention in that Lewis fails to teach adding a second polymer to specifically reverse the high affinity interaction between the linking system (between the first polymer and the ligand that binds the first polymer). Lewis fails to teach the high affinity linking system comprises a nanomolar-scale equilibrium dissociation constant, or lower. Lewis also differs from the claimed invention in that Lewis teach methods comprising binding to fetal microparticles, i.e., those expressing fetal specific protein or antigens (para [0103] of Lewis); and as such the reference fails to teach wherein the exosomes and/or microvesicles expresses one or more of CD9, CD63, CD81, HSPA8, HSC70, selectins and CD40, as recited at the claims.
Dowd et al. also teach methods comprising magnetic particles usable for biological target (namely cell) separation (para [0001]), see the separation methods of Dowd rely on magnetic separation by labeling the targets, such as specific cells, and using a magnetic field gradient of sufficient strength in order to separate the targets from the sample and other entities in a sample suspension including unwanted cells (see paras [0008] and [0013]). Dowd et al. teach method steps consistent with Lewis, in particular steps comprising the same type of linking system (namely binding the biological target to a label that is a magnetic particle label through a linking system comprising a first polymer such as a polysaccharide, i.e. dextran, see para [0016] and [00080]) and a ligand that binds the first polymer, namely a TAC, such as that used in Lewis, see e.g. paras [00012]-[00013], [00016], [00021], [00024], [00032]-[00034], [00061] and particularly paras [00072] and [00076]). At para [0007], Dowd teach a step of separating the bound target cells from other entities (including cells) in a suspension.
The interaction between the polymer (dextran) and a ligand (anti-dextran antibody) for said polymer, namely a TAC, as taught by Lewis and Dowd is considered a specific, immunoaffinity interaction (see for example para [0008] of Dowd; see also Lewis para [0140]). The interaction between the polymer and antibody as described by Dowd is described as sufficiently strong enough to withstand, for example, magnetic particle separation (separation of the target by magnetic force, maintaining interaction with the linking system). See similarly this is the case in Lewis, e.g., para [0007] separating from suspension. As a result, although Dowd and Lewis does not specifically use the language “high affinity”, one having ordinary skill in the art, from the disclosures of Lewis and Dowd, would consider that the binding to the label through the linking system be binding that is achieved through high affinity binding (between polymer and ligand specific for said polymer), at least in so much that the affinity is high enough to prevent separation (can withstand separation in suspension, prior to treatment for release).
The purpose of Dowd is for example to obtain a purified population (paras [0008], [0013]). See Dowd at para [0013], Dowd teaches that non-specific binding occurs during the magnetic separation. See at para [0013] Dowd indicates after magnetic labeling and initial separation, a wash is necessary in order to wash away nonspecifically separated cells. The ordinarily skilled artisan would appreciate from the disclosure of Dowd, that “non-specifically separated cells” are cells that non-specifically adhered during the separation, since this paragraph is referencing cells that were carried over non-specifically following magnetic separation, and further because at para [00095] Dowd does teach particles are subject to non-specific binding to cells (see lines 20-23, in reference to the particles, Dowd teach increased surface area at smaller diameters also increases non-specific binding to the cells). Dowd is therefore considered to also teach that the non-specific binding is binding that occurs between the unwanted cells and the particle itself (is a result of the particle). Further see para [000103], where again Dowd also acknowledges non-specific binding to particles.
Skold et al. teach obtaining pure materials from mixtures by separation using polysaccharide (dextran para [00065]) coated magnetic particles (see e.g. abstract and para [0002])); specifically, Skold teach such separations are crucial to many disciplines (para [0005]), teaching such separation is desirable for diagnostic and therapeutic techniques (abstract, and e.g. para [0003]). At claim 8, Skold specifically teach dissociating magnetic particles bound to target material and removing the magnetic particles to provide a substantially pure preparation of the target material (i.e., further separation of magnetic particles and target cells).
Anastase et al. teach binding anti-dextran antibodies to solid support silica beads by binding antibodies to dextran on said beads (i.e. silica linked with dextran by DEAE-dextran by cross-linkage using 1,4-butanediol diglycidyl ether) (see e.g. abstract, and page 143, col. 1, paras 2 and 3). Anastase teach the act of eluting anti-dextran from dextran conjugated silica by addition of a second dextran polymer the bound anti-dextran antibody (see page 146, col. 1) (i.e. using additional polymer, e.g., in the case of Anastase, dextran used to displace/reverse the binding interaction; it would be the case that the second polymer, by displacing/reversing the binding, is competitively inhibiting binding of the first polymer). As such, Anastase demonstrates it was known in the art at the time of the invention to separate an anti-dextran antibody-dextran bond via addition of more polymeric dextran (i.e., polymer second to that first polymer initially bound) in order to cause displacement, i.e., thereby reversing the interaction (reversing the high affinity interaction).
Lim teach mesenchymal stem cells (MSCs) are multipotent stem cells with documented evidence of therapeutic efficacy in treating musculoskeltal injures, improving cardiac function in cardiovascular disease and ameliorating the severity of GVHD (graft-versus-host-disease). Lim teach human ESC-derived MSCs mediate cardioprotective effects through secreted complexes, particles, exosomes (see page 11, lines 4-26; also page 12, lines 3-5); that these secreted complexes or particles (exosomes) are usable for therapeutic means, including for cardioprotection, in place of the cells themselves (usable for cardia or heart disease such as ischaemia, cardiac inflammation, heart failure, or repair following perfusion injury). Lim teach CD9 as an exosome-associated protein (page 11, line 9), Lim teach CD9 is a commonly expressed protein (end of page 82-83). In particular, see at page 85, Example 41, Lim teach enrichment by way of CD9.
It would have been prima facie obvious to one of ordinary skill in the art before the claimed invention was effectively filed, to have modified the method invention of Lewis et al., in order to further dissociate and separate the magnetic beads from the targeted material following the step of magnetic separation of the targeted microvesicles (extracellular vesicles) from the sample, and further specifically to have performed said separation by addition of a second polymer (contacting magnetically separated targeted microparticles (exosomes and microvesicles) with second polymer), such as another dextran (free dextran), as taught by Anastase et al. (thereby specifically reversing the interaction between the target and the label/magnetic particle by reversing the high affinity interaction of the linking system that is mediating binding).
One would be motivated to further separate the magnetic particle from the rest of the bound complex (the target) because Skold teach it is desirable for diagnostic and therapeutic techniques to recover pure biological target by magnetic separation using polysaccharide coated magnetic particles, and further because Skold teach dissociating particles from target further achieves substantially pure target material. Even further, considering it was known that the particle labels themselves are subject to non-specific binding of unwanted cells in a suspension (see for example, as supported by the teaching of Dowd), one would be further motivated to completely remove the source of any potential non-specific binding (i.e., the particle), specifically to achieve a substantially pure target material (removes any residual or remaining non-specific binding, and further achieves a sample more pure, i.e. pure as in without the particle itself as well).
Moreover, it would have been obvious to have applied the known technique of Anastase et al., namely the technique of using free dextran (second polymer) in order to release bound anti-dextran antibody (to inhibit/separate/reverse the binding between the antibody and the polymer on the label) as an obvious matter of applying a known technique to a known method, since the prior art in view of Lewis, Dowd and Skold recognized the base method of using magnetic separation techniques employing dextran on magnetic particles for the capture of target biological material (such as cells, and cellular material, e.g., microparticles), and Anastase et al. taught that it was a known technique in the art to achieve separation of the bond between dextran and anti-dextran antibody for the purpose of dissociating the antibody from a solid support (competitive displacement by addition of more polymer (dextran)) specifically by applying additional free (second) polymer. One having ordinary skill in the art would have recognized that applying the known technique of Anastase et al. to the base method as taught by Lewis, Dowd and Skold would have predictably yielded the result of separating the bond between the dextran and the anti-dextran, thereby separating target cell from magnetic particle, and in turn increasing the purity of the targeted cells as compared to methods which don’t involve such separation (which, see as discussed previously in detail and above, Skold teaches removing magnetic label in order to achieve substantially pure preparations).
One having ordinary skill in the art would have had a reasonable expectation of success applying the separation technique of Skold, namely removing magnetic particle to obtain substantially pure target by addition of free polymer (dextran), as in Anastase, because Lewis is similarly directed toward the isolation/purification of a biological material target by way of magnetic separation, and because the art (Anastase) supports those having ordinary skill already recognized competitive displacement by way of free dextran as a suitable manner to effectively release anti-dextran bound to solid support by dextran. Therefore, one would expect success because the modifications as set forth in the above analysis do no more than apply art recognized techniques to further improve the isolation/enrichment of a targeted material.
Regarding the claim language, that second polymer is added to reverse the high affinity interaction of the linking system mediating binding of the exosomes and/or microvesicles and the label under conditions that yield exosomes and/or microvesicles i) having a maintained integrity and/or function, and ii) are in a condition for downstream analysis”, the conditions of separation described by the combination of the cited art are those conditions that would achieve exosomes/microvesicles as desired by the present claim language (namely those having maintained integrity and/or function, those capable of downstream applications) because the combination of the cited art is teaching a method comprising displacement using the same reagent in the same way (competitive displacement with second polymer), for the purpose of downstream application (see for example, Skold provides motivation to separate, namely that it is desirable for diagnostic and therapeutic techniques, both of which are considered downstream applications). Since the combination of the art is teaching performing separation in the same way as presently claimed, and for the purpose of removing the particle, it is maintained that it would be expected the combination of the cited art achieves reversal of interaction with the same results, namely under conditions that maintain integrity and/or function of the exosome and/or microvesicle (i.e., the captured component remains intact upon release).
Further, regarding the limitation “wherein the high affinity linking system comprises a nanomolar-scale equilibrium dissociation constant, or lower” (is 1nM or less, claim 9, is 100 M or less, claim 10), see as discussed previously above, the combination of the cited art is describing specific binding between the polymer and the anti-polymer antibody of the linking system. The prior art at recognized specific binding as binding between and antigen and antibody when the dissociation constant is <1µM, preferably <100 nM, most preferably<10 nM (see Greenfeder et al., US PG Pub No. 2003/0194404A1, at para [0040]). Greenfeder is cited as supportive evidence that the specific binding as taught by the combination of the cited art (namely the specific binding between the polymer (first polymer) and the anti-polymer antibody, i.e. the high affinity linking system), comprises nanomolar-scale equilibrium dissociation constant (or lower). As a result, the combination of the cited art addresses the claim.
It would have been further prima facie obvious to one having ordinary kill in the art to have modified the targeted microparticles/exosomes, specifically to have modified the linking system in order to target cellular exosomes such as ESC-derived MSC microparticles (cell exosomes which express, for example CD9), as in Lim. One would be motivated to target ESC-derived MSC microparticles (exosomes expressing CD9) because they were recognized in the art as usable for therapeutic means, including for cardioprotection, in place of the cells themselves (usable for cardia or heart disease such as ischemia, cardiac inflammation, heart failure, or repair following perfusion injury). Further, the modification would be an obvious matter of a simple substitution, specifically modifying the linking system to target one type of microparticle for another (by changing the ligand to which binds the target).
One having ordinary skill would have a reasonable expectation of success in modifying the TAC linking system as indicated above, because the modification would merely require a substitution of the ligand specific for the target (modifying to include ligand specific to these types of particles, for example such as an antibody that binds CD9 as in Lim).
Regarding claim 2, the analysis above addresses wherein the first and second polymer have similar affinity for the ligand, since both the first and second polymer addressed above are dextran.
Regarding claims 3 and 4, the combination of the cited art above addresses a linking system comprising a ligand that binds to the target (the microparticles, i.e., exosomes and microvesicles) linked to a ligand that binds to a first polymer and a label conjugated with the first polymer (see the TAC linking system of Lewis, described above).
Regarding claim 5, see the combination of the cited art teaching a first and second polymer that are each dextran.
Regarding claim 6, see the combination of the cited art teaches a label that is a solid support (magnetic particle, see as cited above).
Regarding claims 7 and 8, see the TAC system of Lewis cited above addresses a ligand that binds the biological target (cell) that is an antibody and the ligand that binds the first polymer is an antibody, the antibodies linked together as a bispecific antibody.
Regarding claim 11, see Anastase at page 143, Anastase describe separation (elution) in PBS (PBS pH 7.2, see for example, Figure 4B and page 146, col. 1, para 3). Anastase report elution (displacement) via the additional polymer (eluted using a specific buffer, dextran in PBS, see page 146).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Lewis et al. in view of Dowd et al, Skold. Anastase et al., Lim, and as evidenced by Greenfeder et al., as applied to claim 1 above, and further in view of Miltenti, WO 96/31776A1 (IDS entered 12/24/2024).
The combination of the cited art teach a method substantially as claimed (see as cited above). As cited above, Anastase does teach releasing in conditions that are polymer provided in PBS (see as cited above, at page 146, referring to Figure 4B, which includes release conditions that are dextran in PBS). In reading Anastase, while downstream applications were performed following dialysis, not all release was performed under dialyzing conditions.
Nonetheless the present rejection is also being made in the interest of compact prosecution, as Anastase could be considered as teaching release that is both displacement coupled with dialysis.
Regarding the limitation of claim 24, namely addition of the second polymer (step 3) under conditions comprising salt concentration and pH substantially the same as PBS, see further Miltenti is another example in the art which further discusses magnetic particle separation, and the desirable subsequent release of particles for further downstream application (for example, further labeling/enrichment, etc., see abstract, page 1, lines 25-26; page 6, lines 6-8). Miltentti, consistent with references cited above teaches following the action of release from a magnetic particle, it is desirable to retain viability (see page 6, lines 6-8, for example with respect to cells, maintaining viability is desirable, for example such that additional affinity reagents can be applied). Regarding medium in which release is performed, see page 6, Miltenti teach medium will be any medium that maintains viability of cells and allows activity of the release reagent (see lines 27-29). Miltenti teach suitable medias include, for example, PBS, dMEM, HBSS, etc. (lines 30-34). Miltenti (page 7, lines 2-5) teach optimizing conditions in terms of temperature, pH, presence of metal cofactors, reducing agents, etc., experimentally.
It would have been prima facie obvious to one having ordinary skill in the art to further have performed the release step (i.e., addition of the second polymer, as in Anastase), when performing the method as taught by the combination of Lewis and the cited art, under conditions consistent with the composition of PBS because PBS-like conditions were conditions recognized by the prior art as suitable for maintaining viability upon release of a cellular target from a magnetic particle (see for example Miltenti). Further, one would be motivated to maintain such conditions that maintain viability in order to retain the target for subsequent analysis, for example such as further affinity binding (as taught by Miltenti). Also, considering PBS was recognized as suitable medium, and because the prior art recognized each of pH and salt concentration as variables that should be optimized experimentally during microparticle separation in order to achieve release of target while maintaining viability and subsequent affinity binding, it would have been further obvious to have optimized these variables such to arrive at a salt concentration and pH that is substantially the same as PBS. This is particularly the case, considering PBS is recognized as medium suitable for achieving this result (achieving viability).
Further, because the prior art specifically recognizes PBS as suitable, and recognizes salt concentration and pH as variables that should be optimized, one having ordinary skill would have a reasonable expectation of success.
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 §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of US Patent No. 12,276,658B2 (previously referred to as Application No. 14/419,665) in view of Lewis et al. (cited previously above) and Lim, and as evidenced by Greenfeder et al.
Although the claims at issue are not identical, they are not patentably distinct from each other because ‘658 similarly recites a method of separating a biological target (target cell) from a label in a sample comprising: binding the biological target to the label through a linking system comprising a first polymer and a ligand that binds to the first polymer, and adding a second polymer to the sample to separate (separate by reversing binding) the biological target from the label (see ‘658 claims 1 and 8, see at claim 8 teaching obtaining a target that is recapturable and with increased purity).
‘658 recites a method substantially as claimed (see detailed analyses above), however the ‘658 fails to recite biological target, namely an extracellular microvesicle or exosome (claim 1). Further fails to teach binding is high affinity binding, the linking system having nanomolar equilibrium dissociation constant or lower, and fails to teach wherein the exosomes and/or microvesicles express one or more of CD9, CD63, CD81, HSPA8, HSC70, selectins and CD40, as recited at the claims.
Lewis et al. is as cited in detail previously above, teaching isolation and detection of fetal DNA containing microparticles (see complete citation previously above, microparticles of Lewis addressing exosomes and microvesicles).
Lim is as cited in detail previously above, teaching mesenchymal stem cells (MSCs) are multipotent stem cells with documented evidence of therapeutic efficacy in treating musculoskeltal injures, improving cardiac function in cardiovascular disease and ameliorating the severity of GVHD (graft-versus-host-disease). Lim teach human ESC-derived MSCs mediate cardioprotective effects through secreted complexes, particles, exosomes (see page 11, lines 4-26; also page 12, lines 3-5); that these secreted complexes or particles (exosomes) are usable for therapeutic means, including for cardioprotection, in place of the cells themselves (usable for cardia or heart disease such as ischaemia, cardiac inflammation, heart failure, or repair following perfusion injury). Lim teach CD9 as an exosome-associated protein (page 11, line 9), Lim teach CD9 is a commonly expressed protein (end of page 82-83). In particular, see at page 85, Example 41, Lim teach enrichment by way of CD9.
It would have been prima facie obvious to one having ordinary skill in the art before the effective failing date of the claimed invention to have modified the ‘658 with Lewis for the same reasons as discussed previously above (see analyses above regarding Clark et al. in view of Lewis et al., as the same reasoning applies presently).
Regarding the recited claim language “high affinity linking system”, the second polymer reversing the “high affinity interaction of the linking system”, see the ‘658, the linking system as claimed is indistinguishable from that taught by the ‘658.
Further, although ‘658 is silent as to whether the second polymer is added “under conditions that yield exosomes and/or microvesicles i) having a maintained integrity and/or function, and ii) in a condition for downstream analysis”, the conditions of separation described by the combination of ‘658 and the cited art conditions that would achieve exosomes/microvesicles as desired by the present claim language (namely those having maintained integrity and/or function, those capable of downstream applications). The combination of the cited art is teaching a method comprising displacement using the same reagent in the same way (competitive displacement with second polymer), and as a result the released target is expected to yield a target similarly with maintained function/integrity, and as such expected capable of downstream analysis.
It would have been further prima facie obvious to one having ordinary kill in the art to have modified the targeted microparticles/exosomes, specifically to have modified the linking system in order to target cellular particles (e.g., exosomes) such as ESC-derived MSC microparticles (cell exosomes which express, for example CD9), as in Lim. One would be motivated to target ESC-derived MSC microparticles (exosomes expressing CD9) because they were recognized in the art as usable for therapeutic means, including for cardioprotection, in place of the cells themselves (usable for cardia or heart disease such as ischaemia, cardiac inflammation, heart failure, or repair following perfusion injury).
One having ordinary skill would have a reasonable expectation of success in modifying the TAC linking system as indicated above, because the modification would merely require a substitution of the ligand specific for the target (modifying to include ligand specific to these types of particles, for example such as an antibody that binds CD9 as in Lim).
Further, regarding the limitation “wherein the high affinity linking system comprises a nanomolar-scale equilibrium dissociation constant, or lower” (is 1nM or less, claim 9, is 100 M or less, claim 10), see as discussed previously above, the combination of the cited art is describing binding between the polymer and an antibody that binds to the polymer of the linking system. The prior art at recognized specific binding as binding between an antigen and antibody when the dissociation constant is <1µM, preferably <100 nM, most preferably<10 nM (see Greenfeder et al., US PG Pub No. 2003/0194404A1, at para [0040]). Because the ‘658 is referring to an antigen and its antibody (a polymer and an anti-polymer antibody) it would therefore be expected that binding have nanomolar equilibrium dissociation constant or lower as claimed. Further, see the ‘658 is teaching the same type of binding and the same type of linking system, supporting one would reasonably expect the same high affinity binding.
Regarding claim 2, see ‘658 claims 2 and 9.
Regarding claims 3 and 4, see ‘658 claim 1.
Regarding claim 5, see ‘658 claims 3 and 10.
Regarding claim 6, see ‘658 claims 4 and 11.
Regarding claims 7 and 8, see ‘658 claim 1.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of US 12,276,658B2 in view of Lewis et al. (cited previously above) and Lim, and as evidenced by Greenfeder et al., as applied to claim 1, and further in view of Miltenti.
Regarding the limitation of claim 11, ‘658 is silent as to the condition in the step of adding a second polymer, namely fails to teach addition of the second polymer (step 3) under conditions comprising salt concentration and pH substantially the same as PBS.
Miltenti is as cited previously above, and is another example in the art which further discusses magnetic particle separation, and the desirable subsequent release of particles for further downstream application (for example, further labeling/enrichment, etc., see abstract, page 1, lines 25-26; page 6, lines 6-8). Miltentti, consistent with references cited previously (and also above) teaches following the action of release from a magnetic particle, it is desirable to retain viability (see page 6, lines 6-8, for example with respect to cells, maintaining viability is desirable, for example such that additional affinity reagents can be applied). Regarding medium in which release is performed, see page 6, Miltenti teach medium will be any medium that maintains viability of cells and allows activity of the release reagent (see lines 27-29). Miltenti teach suitable medias include for example PBS, dMEM, HBSS, etc. (lines 30-34). Miltenti (page 7, lines 2-5) teach optimizing conditions in terms of temperature, pH, presence of metal cofactors, reducing agents, etc., experimentally.
It would have been prima facie obvious to one having ordinary skill in the art to further have performed the release step (i.e., addition of the second polymer, as in ‘658), when performing the method as taught by the combination of the ‘658 and the cited art, under conditions consistent with the composition of PBS because PBS like conditions were conditions recognized in the art as suitable for maintaining viability upon release of a cellular target from a magnetic particle (see for example Miltenti). Further, one would be motivated to maintain such conditions that maintain viability in order to retain the target for subsequent analysis, for example such as further affinity binding (as taught by Miltenti). Also, considering PBS was recognized as suitable medium, and because the art recognized each of pH and salt concentration as variables that should be optimized experimentally during microparticle separation in order to achieve release of target while maintaining viability and subsequent affinity binding, it would have been further obvious to have optimized these variables such to arrive at a salt concentration and pH that is substantially the same as PBS. This is particularly the case, considering PBS is recognized as medium suitable for achieving this result (achieving viability). Because the art specifically recognizes PBS as suitable, and recognizes salt concentration and pH as variables that should be optimized, one having ordinary skill would have a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Correspondence
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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