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 .
Applicants’ response of 7/21/2026 has been received and entered into the application file.
Claims 8-10, 12-20, and 22-30 are pending, all of which have been considered on the merits.
Specification
It is acknowledged Applicants submitted a petition for acceptance of color drawings. The petition is in queue for review by the appropriate department. The objection to the drawings is maintained until the petition is granted. A separate communication will be sent regarding the petition decision.
The drawings submitted 7/12/2022 and 7/21/2026 are objected to because they contain color images without a granted petition to accept color images.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Updated Claim Interpretation
Independent claims 8 and 19 are directed to methods for generating extracellular vesicle (EVs) educated macrophage or EV educated monocytes, respectively, comprising:
culturing isolated MSCs expressing TLR4 in stem cell media, the stem cell media comprising LPS;
harvesting the stem cell media;
isolating EVs from the stem cell media of (b), and then
co-culturing a CD14+ cell with the EVs isolated in step (c) in vitro until the CD14+ cell acquires an anti-inflammatory macrophage or monocyte phenotype, respectively.
MSCs are available from a variety of tissue sources, e.g. bone marrow, peripheral blood, adipose tissue, dermal tissue, umbilical cord blood, Wharton’s jelly, amnion, dental pulp, and more. Thus, MSCs are considered a genus of cells. The scope of MSCs expressing TLR4 is a sub-genus of those cells, as not all MSCs express TLR4. Specifically, Raicevic et al (Cell Immunol, 2011) shows that bone marrow-MSCs (BM-MSCs) and adipose-MSCs (AT-MSCs), but not WJ-MSCs express TLR4 (See Raicevic et al, section 3.2, also Pg 211, col. 2, second paragraph). Najar et al (Immune Network, 2017) repeats this finding, and adds on that umbilical cord blood-derived MSCs (CB-MSCs), human amnion-derived MSCs and dental MSCs all express TLR4 (See Najar et al, Pg 92, col. 2). Thus, the modified scope of claims 8 and 19 is specifically excluding, at least, WJ-MSCs.
The term “extracellular vesicle (EV)” is defined in the specification as referring to both exosomes and micro-vesicles (See ¶0047). The independent method claims require isolation of EVs, thus co-culture of CD14+ cells with mesenchymal stem cells, per se, that have previously been exposed to LPS will not read on the method(s).
Independent claims 16 and 27 are written as product-by-process claims. Product-by-process claims are considered only in so far as the process of production affects the final structure of the product. Thus, the cells of claims 16 and 27 must have the phenotype imparted by the product-by-process limitations as well as the specific phenotype recited by each respectively claim.
Applicants provide comparison between macrophages and monocytes ‘educated by’ (i.e. co-cultured with) EVs derived from LPS-primed MSCs (referred to in the instant specification as “LPS-EEMs” or “LPS-EEMos”, respectively) and macrophages and monocytes educated by EVs from non-LPS-primed MSCs (referred to in the instant specification as simply “EEMs” or “EEMos”, respectively). At least Fig. 3A and Table 4 support that LPS-EEMs differ from EEMs. At least Fig. 5A and 5B support that LPS-EEMos differ from EEMos. These same figures and tables support that macrophages educated by EVs derived from MSCs primed with high versus low concentrations of LPS cause a material change in the phenotype of LPS-EEMs and LPS-EEMos. This supports that the process of production does impart specific structural limitations to the claimed cells.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 10, 11, 13, and 22-24 under 35 USC 112(b): The amendments to the claims are overcome the previous rejections. The rejections are withdrawn.
RE: Rejection of claims 12-13 and 22-24 under 35 USC 112(d):
The amendments to the claims are overcome the previous rejections. The rejections are withdrawn.
RE: Rejection of claims 8-17 and 19-27 under 35 USC 102(a)(1) as being anticipated by Ti et al:
Applicants have amended the independent claims to limit the MSCs used to produce the EVs to MSCs that express TLR4. Applicants assert their specification teaches use of BM-MSCs (which do express TLR4, according to Raicevic et al (Cell Immunol, 2011). Applicants assert Ti et al use umbilical cord-MSCs, which contain WJ-MSCs, which do not express TLR4 according to Raicevic et al.
It is first noted the claims are not limited to BM-MSCs, but the claims do exclude at least WJ-MSCs for the reasons discussed above.
It is second noted that Ti et al do not specify that the umbilical cord MSCs are WJ-MSCs (umbilical cord-derived MSCs include WJ-MSCs, cord blood-derived MSCs, and amnion-derived MSCs). Najar et al (Immune Network, 2017) evidence that cord blood-derived MSCs and amnion-MSCs both express TLR4 (See Najar et al, Pg 92, col. 2). Thus the argument that because umbilical cord contains WJ-MSCs means the MSCs of Ti et al don’t satisfy the claim limitation is not persuasive on its own. However, Ti et al teach isolation of UC-MSCs by “processing human umbilical cord tissue as described by Professor Hou et al. [22].” (Ti et al, Pg 3 “Isolation, culture and LPS-preconditioning of MSCs”). Hou et al (Mol Med Rep 2015) teaches isolating UC-MSCs from human umbilical cord tissues by obtaining umbilical cords, removing the umbilical vessels and external membrane, then cutting the tissue into 1 mm3 samples (See Hou et al, Pg. 2522 “Preparation of hUCMSCs”). Removal of the umbilical vessels means the cord blood was not used. Removal of the external membrane means the umbilical cord amnion was not used. This leaves the Wharton’s jelly as the tissue being processed as the source of the UC-MSCs. Therefore the UC-MSCs isolated by Hou et al, and by Ti et al, are WJ-MSCs. As the claims now exclude WJ-MSCs, the rejection is withdrawn.
RE: Rejection of claim 18 under 35 USC 103 over Ti et al:
Ti et al does not anticipate base claim 8 for the reasons set forth above. The rejection is withdrawn.
RE: Rejection of claims 8-11 and 13-27 on grounds of NSDP over US Patent 11499730:
Applicants did not traverse the rejection. The rejection has been modified to address current claims.
New/Modified Claim Rejections
Claim Objections
Claim 20 is objected to for a minor informality:
In claim 20, line 4, the word “same” should be removed (so as to read …replaced with fresh media in step (a) in each cycle…”).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 8-10, 12-20 and 22-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 8 and 18 have been amended to require an active step of culturing isolated MSCs to produce EVs. The claims now limit the MSCs to those species that express TLR4. Limiting the claims to MSCs that express TLR4 defines a narrowed sub-genus of MSCs. As discussed above, MSCs are available from a variety of tissue sources, e.g. bone marrow, peripheral blood, adipose tissue, dermal tissue, umbilical cord blood, Wharton’s jelly, amnion, dental pulp, and more. Thus MSCs can be considered a genus of cells. The scope of MSCs expressing TLR4 is a sub-genus of those cells, as not all MSCs express TLR4. Specifically, Raicevic et al (Cell Immunol, 2011) shows that bone marrow-MSCs (BM-MSCs) and adipose-MSCs (AT-MSCs), but not WJ-MSCs express TLR4 (See Raicevic et al, section 3.2 and also Pg 211, col. 2, second paragraph). Najar et al (Immune Network, 2017) repeats this finding, and adds on that umbilical cord blood-derived MSCs (CB-MSCs), human amnion-derived MSCs and dental MSCs all express TLR4 (See Najar et al, Pg 92, col. 2). The original disclosure does not provide support for this narrowed sub-genus of MSCs. Thus it is not reasonably conveyed that the inventors had possession of the currently claimed invention.
The original disclosure teaches “MSCs… for use in the methods or compositions of the present invention may be derived or isolated from any suitable source. MSCs … may be isolated from tissues including but not limited to bone marrow, lung, cornea, intestines, testis, tendon, adipose, muscle, liver, vertebral, umbilical, and amniotic. In one embodiment, MSCs are isolated from bone marrow (BM-MSCs).” (¶0043). The original disclosure does not envisage or identify any narrower subgenus of MSCs based on TLR4 expression. The only mentions of TLR4 in the original disclosure are in ¶0046, where the specification teaches LPS is a TLR4 ligand, and identifies alternative TLR4 ligands can be used in place of LPS, and a mention at ¶0081 where LPS is again identified as a TLR4 ligand. Therefore, introduction of this narrowing limitation into claims 8 and 18 is considered new matter. The new matter must be removed in response to this office action. Applicants are advised that the introduction of the new matter has necessitated withdrawal of one or more prior art rejections, and removing the new matter may result in reinstatement of the prior art rejections.
The cells of claims 16 and 27, the pharmaceutical compositions of claim 28, and methods of use of claim 29, all incorporate limitations from claims 8 or 18, and thus inherit the deficiency.
It is noted that Applicants do have support for use of BM-MSCs, and do have support for umbilical cord MSCs (generically. Applicants do not explicitly recognize Wharton’s jelly MSCs. Disclosure of umbilical [tissue] as the source of MSCs is not sufficient to support Wharton’s jelly MSCs, as umbilical tissue includes Wharton’s jelly MSCs, umbilical cord blood MSCs and umbilical cord amnion MSCs). Applicants may limit their claims to use of BM-MSCs or may explicitly exclude MSCs from [generic] umbilical tissue.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 8-10, 13-20 and 23-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11499730, in view of Raicevic et al (Cell Immunity, 2011).
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims anticipate and/or render obvious the instant claims as follows:
Regarding claims 8, 9 and 13: Patented claim renders obvious instant claims 8, 9 and 13. Patented claims 8, 9 and 13 teach isolating EVs from an MSC that was previously exposed to LPS. While the patented claims don’t teach active steps of culturing MSCs or harvesting the EV-containing media therefrom, these steps are required to be performed for successful operation of the patented method, and thus rendered obvious by the patented method(s).
The patented methods differ from the instant claims in that they do not specify the MSCs are ones that express TLR4. However, given that the MSCs are cultured with LPS (which is a TLR4 ligand), and the effect on the EVs is due to the culture with the LPS, it would have been prima facie obvious to have selected an MSCs known to express a TLR4 ligand. Raicevic et al teach that BM-MSCs express TLR4 ligand (See section 3.2). Therefore, it would have been prima facie obvious to have selected BM-MSCs as the MSCs for carrying out the patented method. It is further noted that BM-MSCs are the exemplified cell type in the patent. It is permissible to look to the specification of the patent to determine the scope of the patented claims. Use of BM-MSCs as the type of MSCs from which the EVs are derived is thus prima facie obvious over the patented claims.
Regarding claim 10: The steps of current claim 10 is considered prima facie obvious as a matter of routine optimization. Repeating culture and harvest of factor-containing conditioned media to optimize recovery is well known by those of ordinary skill in the art.
Regarding claim 14: Given the MSC-EVs are produced by the same method as described in the instant application, there is reasonable basis to conclude that the EVs, per se, have the same markers as required by claim 14.
Regarding claim 15: Patented claim 2 teaches the CD14+ cells and the EVs are co-cultured for at least 2 days.
Regarding claim 17: Patented claim 4 teaches the limitations of claim 17.
Regarding claim 18: Patented claim 5 teaches the limitation of claim 18.
Regarding claim 16: Patented claim 6 is describing LPS-high-EEMs, which anticipate the cells of current claim 16.
Regarding claim 28: Following the discussion of claim 16 above, further inclusion of a pharmaceutically acceptable carrier with the cells is prima facie obvious.
Regarding claims 29-30: Patented claim 6 describes the LPS-high-EEMs, which are considered to be the same as the anti-inflammatory macrophages of current claim 16. The patent also teaches that the anti-inflammatory macrophages of invention can be used to treat a variety of radiation-induced disorders, including each of those recited in claim 30 (See col. 12, ln 41-col. 13, ln 61). It has been held that a claim to a method of using a composition is not patentably distinct from an earlier claim to the identical composition in a patent disclosing the identical use. See Pfizer, 518 F.3d at 1363; Geneva, 349 F.3d at 1385-86, and Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F. 3d 1381, 1387 (CAFC 2010). See MPEP 804(II)(B)(1).
Regarding claims 19, 23: Patented claim 7 renders obvious claim 19 in an equivalent manner that patented claim 1 renders obvious claim 8.
Regarding claim 20: The steps of current claim20 is considered prima facie obvious as a matter of routine optimization. Repeating culture and harvest of factor-containing conditioned media to optimize recovery is well known by those of ordinary skill in the art.
Regarding claim 24: Given the MSC-EVs are produced by the same method as described in the instant application, there is reasonable basis to conclude that the EVs, per se, have the same markers as required by claim 24.
Regarding claim 25: Patented claim 8 teaches the limitations of claim 25.
Regarding claim 26: Patented claim 9 teaches the limitation of claim 26.
Regarding claim 27: Patented claim 11 is describing LPS-high-EEMo, which anticipate the cells of current claim 27.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M FOX whose telephone number is (571)272-2936. The examiner can normally be reached M-F 10-6 EST.
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/ALLISON M FOX/Primary Examiner, Art Unit 1633
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