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 .
The preliminary amendment filed 1/17/2025 has been received and entered into the application file. Claims 8-27 are pending, all of which have been considered on the merits.
Priority
Acknowledgement is made of Applicants’ claim for benefit as a continuation of prior-filed US application NO. 16/273712 (filed 2/12/2019, now USP 11499730), which claims benefit of prior-filed US Provisional application 62/629479 (filed 2/12/2018).
Specification
The drawings submitted 7/12/2022 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).
Claim Interpretation
Independent claims 8 and 19 are directed to methods for generating extracellular vesicle (EVs) educated macrophage or EV educated monocytes, respectively, comprising:
isolating EVs from media of mesenchymal stem cells (MSCs) cultured in media containing LPS, and then
co-culturing a CD14+ cell with the [isolated] EVs in vitro until the CD14+ cell acquires an anti-inflammatory macrophage or monocyte phenotype, respectively.
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.
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 10, 11, 13 and 22-24 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.
Regarding claims 10, 11, 20 and 21: It is unclear how the step of harvesting and replacing the stem cell media fits into the method of parent claims 8 and 19, respectively. The method of parent claims 8 and 19 do not involve an active step of culturing the MSCs in stem cell media containing LPS, but rather only recites a step of isolating EVs from stem cell media of MSCs cultured in the presence of LPS. While it is permissible for claims 10 and 20 to further define the culture conditions by which the EVs are produced, these process steps would be treated as product by process limitations. It is noted that once the EVs are isolated (harvested), it would be immaterial how the MSCs/stem cell media/LPS is further treated (e.g. whether it is replenished or not).
It is further noted it is not understood by the phrase “fresh stem cell media is exposed to LPS”. Media is not exposed to an agent, media either contains an agent or it does not.
Regarding claim 11: Claim 11 depends from itself. It appears it should depend from claim 10. If interpreted as being dependent on claim 10, it is not clear how the limitations of claim 11 further limit parent claim 8. It is not clear how repeating a harvest/replacement cycle affects the isolated EVs used in the method of claim 8.
Regarding claim 21: There is insufficient antecedent basis for the limitation “the stem cell media harvest and replacement”. It appears claim 20 should depend from claim 20. If interpreted as being dependent on claim 20, it is not clear how the limitations of claim 21 further limit parent claim 19. It is not clear how repeating a harvest/replacement cycle affects the isolated EVs used in the method of claim 19.
Regarding claims 22-24: It appears claims 22 and 23 were intended to further limit the LPS concentration in which the MSCs were cultured, but they do not actually do so. It is unclear what (if any) limitations claims 22-23 impart to the claims. Claim 24 inherits the deficiency and is rejected on the same basis.
Regarding claims 13 and 23: It is further noted that the range recited in claims 13 and 23 (20-1200 ng/mL LPS) encompasses values lower than the range of claims 12 and 22 (50-200 ng/mL LPS), yet claims 13 and 23 state that 20-1200 ng/mL LPS yields LPS-high EVs. This does not make sense if values of 50-200 ng/mL LPS yield LPS-low EVs, then how would values of 20-200 ng/mL LPS also yield LPS-high EVs? (Perhaps claims 13 and 23 intended to recite a range of 800-1200 ng/mL (mirroring claim 9)?)
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 12-13 and 22-24 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claims 12-13: These claims do not recite additional steps or limitations to the method, but rather appear to recite inherent outcomes of performing the method of claim 9. Recitation of inherent outcomes does not further limit the claim.
Regarding claims 22-24: It does not appear these claims are further limiting the method of claim 19 (i.e. the claims don’t specify that the MSCs were exposed to 50-200 ng/mL or 20-1200 ng/mL LPS).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 8-17 and 19-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ti et al (J Translational Med, 2015), in light of Aldo et al (ARJI, 2013).
Ti et al study the therapeutic efficacy and mechanisms of LPS-preconditioned MSC-derived exosomes (LPS pre-Exo) for chronic inflammation and wound healing (See abstract).
Ti et al collect umbilical cord MSCs, pre-condition the MSCs by incubating with 100 ng/mL LPS for 2 days, collect the supernatant, and then collect the exosomes from the supernatant (LPS pre-Exo). Exosomes collected from MSCs not incubated with LPS was used as a control (un-Exo) (see Ti et al, Pg. 3, “Isolation, culture and LPS-preconditioning of MSCs” and “Exosome extraction and identification”). THP-1 monocytes were cultured under conditions which cause differentiation to CD14+ cells (monocytes and macrophages) (See Ti et al, Pg 3 “THP-1 cell culture and treatment” and Aldo et al, Pg. 3 “Differential response of THP-1 cells”). The differentiated THP-1 cells were cultured in the presence of LPS pre-Exo or un-Exo for 48 hrs (See Ti et al, Pg. 3, “THP-1 cell culture and treatment”). Ti et al report that LPS pre-Exo treatment caused the THP-1 cells to produce dramatically more anti-inflammatory cytokines (IL-10 and TGF-ß) and M2 macrophage surface marker CD163, and less pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) after 48 hrs than control THP-1 cells or THP-1 cells treated with un-Exo (See Ti et al, Pg. 6 and Fig. 3a-b).
The method of Ti et al reads on the instant claims as follows:
Regarding claims 8 and 19: The LPS pre-Exo reads on extracellular vesicles isolated from stem cell media of mesenchymal stem cells previously cultured in stem cell media containing LPS. The THP-1 cells following culture with PMA read on CD14+ monocytes and macrophages (as evidenced by Aldo et al).
The method of Ti et al involves isolating the LPS pre-Exo (extracellular vesicles from stem cell media of mesenchymal stem cells previously cultured in stem cell media containing LPS), and co-culturing the CD14+ cells with the [isolated] extracellular vesicles in vitro. The method results in formation of cells which express increased levels of anti-inflammatory cytokines, which means the CD14+ cells acquired an anti-inflammatory macrophage phenotype.
Regarding claims 9 and 12-13: Ti et al teaches culturing the MSCs in media containing 100 ng/mL LPS. 100 ng/mL is within the scope of claims 9, 12 and 13.
Regarding claims 10-11 and 20-24: As these claims do not clearly require additional limitations, they are included in the rejection of base claims 8 and 19.
Regarding claim 14: Given the LPS pre-Exosomes 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 claims 15 and 25-26: the THP-1 cells and the LPS pre-Exo are co-cultured for 48 hrs (2 days, which is at least 2 hrs, and at least 24 hrs).
Regarding claim 17: The THP-1 cells following culture with PMA read on CD14+ macrophages (as evidenced by Aldo et al).
Regarding claims 16 and 27: The method of Ti et al carries out the same steps as current claims 8, 9, 13 and 19, thus there is reasonable basis to conclude that the method of Ti et al produces the same cells, specifically cells having the phenotype of claims 14, 16 and 27. Though Ti et al do not identify the M2 macrophages as having all markers recited in claim 5, given that the method of production is the same, the phenotypes are necessarily the same. See MPEP 2112.01
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 18 is rejected under 35 U.S.C. 103 as being unpatentable over Ti et al (J Translational Med, 2015), in light of Aldo et al (ARJI, 2013).
The teachings of Ti et al are set forth above. Ti et al anticipates at least claim 8.
Regarding claim 18: In the method of Ti et al, the THP-1 cells are cultured under conditions that give rise to CD14+ monocytes. Monocytes give rise to macrophages. Thus, the method of Ti et al involves culturing CD14+ monocytes with the EVs until the CD14+ acquires the phenotype of a CD14+ pro-inflammatory macrophage.
The method of Ti et al differs from claim 18 in that Ti et al only co-culture the THP-1 cells with the EVs for 48 hrs, not for 5 days. However, culture duration will be recognized by one having ordinary skill in the art as result effective variable that can be routinely optimized. Cell culture involves optimization of a plurality of variables, including culture duration, cell concentration, media type, concentration of agents that affect cell growth (e.g. EV) and temperature. Each of these variables can be manipulated to accommodate technician scheduling and viability while still maintaining the same endpoint. As such, stretching out the duration to at least 5 days from 2 days would have been an obvious modification that does not rise to the level of inventiveness.
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 8-11, 13-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11499730.
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 1 anticipates instant claims 8, 9 and 13.
Regarding claims 10-11: As these claims do not clearly require additional limitations, they are included in the rejection of base claim 8.
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 19: Patented claim 7 anticipates claim 19.
Regarding claims 20-24: As these claims do not clearly require additional limitations, they are included in the base rejection of claim 19.
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.
Relevant Prior Art
The following references were cited on IDS, the following comments are made part of the record:
Hematti et al (US PGPub 2018/0282698) discloses three types of “educated macrophages”: (i) macrophages educated by co-culture with an MSC (‘MSC-educated macrophages’ (MEMs)); (ii) macrophages educated by co-culture with EVs isolated from bone marrow MSCs (‘bone marrow-MSC EV-educated macrophages’ (BM-EEMs)), and (iii) macrophages educated by co-culture with EVs isolated from cardiac fibroblasts (‘cardiac fibroblast EV-educated macrophages’ (CF-EEMs)). The generation of the (ii) BM-EEMs and (iii) CF-EEMs are comparable to the methods of the instant claims, except the BM-MSCs and CFs are not first primed by exposure to LPS. The (ii) BM-EEMs described by Hematti et al are the same as the “EEMs” described in the instant specification. At least Fig. 3A and Table 4 of the instant specification support that LPS-EEMs differ from EEMs (i.e. BM-EEMs of Hematti et al). Thus the (ii) BM-EEMs of Hematti et al do not read on the population of anti-inflammatory macrophages of instant claim 16. Notably, the (ii) BM-EEMs of Hematti et al have lower CD16 expression compared to control macrophages (See Hematti et al, Table 1), whereas the anti-inflammatory macrophages of current claim 5 have higher CD16 compared to control macrophages. Furthermore, the instant specification shows that the EEMs (i.e. BM-EEMs of Hematti et al) have significantly lower FLT-3L expression than the LPS-high-EEMs (the macrophages of instant claim 7; see Table 4 of the instant specification).
Yao et al (J Biomed Sci, 2009) disclose pre-conditioning MSCs with LPS, and then administering the conditioned MSCs to a rat model of acute myocardial infarction. The MSCs are pre-conditioned with various doses of LPS, including 0.1 µg/mL (100 ng/mL) and 1.0 µg/mL (1000 ng/mL). The pre-conditioned MSCs will necessarily produce extracellular vesicles upon introduction in vivo. The extracellular vesicles produced in vivo will necessarily come into contact with some macrophages and/or monocytes within the animal model. However, because the method of Yao et al does not involve administration of isolated extracellular vesicles from the LPS pre-conditioned MSCs, the method of Yao et al does not read on the method of instant claims 8 or 19. Furthermore, because the degree/time of contact between the secreted EVs from the primed MSCs and macrophages/monocytes in vivo is unknown, it cannot be held that the EVs will necessarily cause macrophages and/or monocytes in vivo to acquire the particular anti-inflammatory phenotype required by claims 16 or 27.
Conclusion
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