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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed February 25, 2026.
Claims 1-2, 7-9, and 11-30 are pending in the application. No claims have been canceled, no claims are amended and claims 29 and 30 are newly added by Applicants’ amendment filed on 02/25/2026.
Claims 18-25 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 03/11/2024.
Therefore, claims 1-2, 7-9, 11-17 and 26-30 are examined on the merits.
Priority
This application is a DIV of 16/087,559 filed 09/21/2018 (now ABN). 16/087,559 is a 371 of PCT/IB2017/000412 filed 03/24/2017. Applicant’s claim for the benefit of a prior-filed provisional application 62/336,907 filed 05/16/2016 and 62/313,002 filed 03/24/2016 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Thus, the earliest possible priority for the instant application is March 24, 2016.
Response to arguments
Maintained rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Regarding claim interpretation, claim 1 is a product claim comprising exosomes said exosomes presenting a population profile of miRNA comprising: has-miR- 21-5p, hsa-miR-45la, hsa-miR-103a-3p, hsa-miR-29b-3p, and hsa-miR-101-3p, wherein said exosomes are secreted by umbilical cord blood mononuclear cells conditioned under hypoxic conditions of 0.5% 02, 5% CO2, the conditioned UCBMNCs comprising of monocytes and lymphocytes. Additionally, because the instant claims are product by process claims the exosomes secreted by other cell types such as mononuclear cells (MNCs) comprising lymphocytes and monocytes are within the broadest reasonable interpretation of claim 1 even if the one population of exosomes positively recited within the compositions is obtained from monocytes and lymphocytes of UCBMNCs.
Also exosomes’ profile of miRNA required in claim 1 is not limited to only hsa-miR-21-5p, hsa-miR-45la, hsa-miR-103a-3p, hsa-miR-29b-3p, and hsa-miR-101-3p, but can include additional hsa-miR as disclosed in claims 8 and 9 (See page 8 of Applicants’ remarks filed 10/24/2025) .
Claim 1-2, 7-9, 11-17, and 26-28 are rejected and claims 29-30 are newly rejected under 35 U.S.C. 103 as being unpatentable over Sahoo (US2012/0093885; IDS Reference; previously cited) in view of Sahoo2 (2014. Circulation Research, 114(2): 333-344), Salomon (PLOS ONE 8(11): e79636), King (BMC Cancer 2012, 12:421) and Ismail (2013. Blood (121) 6: 984-99; previously cited) as evidenced by miRbase (miRNAbase (MiRNAbase.org; “Stem-loop sequence hsa-let-7a-1” accessed 11/23/2022).
This rejection has been modified as necessitated by the amendment and arguments filed 02/25/2026.
Regarding claims 1, 2, 7, Sahoo teaches exosomes obtained from mononuclear cells (MNC) wherein the MNC (which comprises lymphocytes and monocytes) can be isolated from umbilical cord blood utilized for regenerative therapy wherein the therapy can be administered to a patient wherein the patient requires wound healing and skin tissue repair wherein the patient has a wound, ulcer, or burns (para. 0008, 0136, 0064, 0071, Abstract). Additionally, Sahoo teaches that these exosomes comprise miRNA such as: hsa-miR-181a (p. 14, Table 2, 2nd column), hsa-miR-17 (p. 16, Table 2, 1st column), hsa-let-7a (p. 17, Table 2, 1st column), hsa-let- 7f (p. 17, Table 2, 2nd column), hsa-mir-20a (p. 18, Table 2, 1st column), hsa-miR-19b (p. 20, Table 2, 2nd column), hsa-miR-30d (p. 22, Table 2, 1st column), hsa-miR-146b-5p, hsa-mir 26a, and hsa-mir-19a (p. 22, Table 2, 2nd column). As evidenced by miRbase, as the probeset of Sahoo indicates “star” or “*” annotation on particular probes, which is known in the art to refer to the 3p designation, (“Mature sequence hsa-let-7a-5p” & “Mature sequence hsa-let-7a-3p”; Previous IDs), the miRNA discussed above is interpreted to be -5p in the absence of the “star” designation. The cells are cultured in a suitable culture medium which is serum free (i.e. without FBS) (para. 0091).
However, Sahoo does not teach conditioning the mononuclear cells (MNC) obtained from umbilical cord blood through hypoxia at levels of 0.5% oxygen and 5% Carbon dioxide in order to produce the claimed exosomes comprising all of the claimed miRNA of claim 1. Additionally, while Sahoo teaches a subset of exosomal miRNA, Sahoo does not teach the specific recited five hsa-miR recited in claim 1.
Sahoo2 teaches that it is known in the art to culture cells such as cardiac myocytes hypoxic conditions in order to alter the rate of secretion of exosomes and increase certain levels of miRNA (p. 340, 1st paragraph; Table, p. 339).
The combined teachings of Sahoo and Sahoo2 do not disclose the specific recited five hsa-miR recited in claim 1, nor the specific hypoxic culture parameters of 0.5% oxygen and 5% CO2.
However, Salomon teaches that exosome secretion is influenced by oxygen tension (i.e. hypoxia) which is consistent across multiple cell types including cardiac monocytes in providing 5 to 7 fold increases in exosome production when compared to normoxic conditions (p. 22, 2nd column). In their experiments, oxygen content of 1%, 3% and 8% with 5% CO2 were tested on MSCs to demonstrate the fold increase (p. 6, 1st paragraph). Particularly the 1% O2 exosomes had enhanced signaling over that of the 3% and 5% (Figure 7).
Additionally, King teaches subjecting different cancer cell lines to 0.1% O2 which resulted in a significant increase in the number of exosomes present in the conditioned media (Abstract, Figure 3; p. 2, column 2; p. 6, 1st column).
Moreover, Ismail teaches that microvesicle production is enhanced by environmental stimuli such as hypoxia (p. 984, 1st column). As evidenced by Ismail, monocyte derived exosomal miRNA comprises hsa-mir-223, hsa-mir-191, hsa-mir-16, hsa-mir-150, hsa-mir-026a, hsa-mir-19b, hsa-mir-146b, hsa-mir-20a, hsa-mir-021, hsa-mir-142-3p, hsa-mir-142-5p, hsa-mir-15b, hsa-mir-29a, hsa-mir-19a, hsa-mir-15a, hsa-mir-30d, hsa-let-7a, hsa-mir-17-5p, hsa-let-7g, hsa-mir 29b, hsa-mir-103 (Table 4, Figure 6). Because, Ismail teaches that exosomes derived from monocytes present the cited profile of miRNA which overlap the exosome miRNA of the present invention in both claims 1 and 8-9 at least for hsa-mir-021, hsa-mir 29b and hsa-mir-103, the presence of the claimed five miRNA of claim 1, hsa-miR-21-5p, hsa-miR-451a, hsa-miR-103a-3p, miR-29b-3p, and hsa miR-101-3p would inherently be present in exosomes derived from monocytes since the process for conditioning monocytes in Isamil is the same as the step claimed in the instant invention absent evidence to the contrary.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to culture the cells of Sahoo in hypoxic conditions as taught by Sahoo2, Salomon, King and Ismail with a reasonable expectation of success. An artisan would have been motivated to utilize hypoxic conditions as Sahoo2, Salomon, King and Ismail teach that it is well known in the art to induce and/or enhance secretion of exosomes by hypoxia. Furthermore, it would be a case of routine optimization given the results of Salomon and King to arrive at 0.5% O2 and 5% CO2 based on Salomon’s teachings that oxygen tension which is found when oxygen decreases, results in enhanced exosome functions and enhances their secretion. Therefore, an artisan would be motivated to routinely optimize the oxygen conditions to produce exosomes from the 1% O2 of Salomon and the 0.1% O2 of King. It is well settled that routine optimization is not patentable, even if it results in significant improvements over the prior art. In support of this position, attention is directed to the decision in In re Aller, Lacey, and Haft, 105 USPQ 233 (CCPA 1955): Normally, it is to be expected that a change in temperature, or in concentration, or in both, would be an unpatentable modification. Under some circumstances, however, changes such as these may impart patentability to a process if the particular ranges claimed produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art. In re Dreyfus, 22 C.C.P.A. (Patents) 830, 73 F.2d 931,24 USPQ 52; In re Waite et al., 35 C.C.P.A. (Patents) 1117, 168 F.2d 104, 77 USPQ 586. Such ranges are termed "critical" ranges, and the applicant has the burden of proving such criticality. In re Swenson et al., 30 C.C.P.A. (Patents) 809, 132 F.2d 1020, 56 USPQ 372; In re Scherl, 33 C.C.P.A. (Patents) 1193, 156 F.2d 72, 70 USPQ 204. However, even though applicant's modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art. In re Sola, 22 C.C.P.A. (Patents) 1313, 77 F.2d 627, 25 USPQ 433; In re Normann et al., 32 C.C.P.A. (Patents) 1248, 150 F.2d 708, 66 USPQ 308; In re Irmscher, 32 C.C.P.A. (Patents) 1259, 150 F.2d 705, 66 USPQ 314. More particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Swain et al., 33 C.C.P.A. (Patents) 1250, 156 F.2d 239, 70 USPQ 412; Minnesota Mining and Mfg. Co. v. Coe, 69 App. D.C. 217, 99 F.2d 986, 38 USPQ 213; Allen et al. v. Coe, 77 App. D. C. 324, 135 F.2d 11,57 USPQ 136. (Emphasis added). With regards to determining experimental parameters, such as time in culture, the court has held that "[d]iscovery of optimum value of result effective variable in known process is ordinarily within skill of art (In re Boesch and Slaney, 205 USPQ 215 (CCPA 1980)).
The adjustment of particular conventional working conditions (e.g., oxygen concentration) is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan having the cited reference before him/her.
Regarding all of the miRNA claimed, while Sahoo, Sahoo2, King, Salomon and Ismail do not explicitly teach each and every miRNA, as the combined references reach on each and every step, the same process parameters yield the same exosomes with the same markers and miRNA content with a reasonable expectation of success.
Regarding claims 8-9, in light of the specification on p. 14-15, it is interpreted that the miRNA is enriched by “using conventional methods known in the art including but not limited to differential centrifugation, density gradient/cushion centrifugation, size- exclusion chromatography, precipitation, immuno affinity capture on beads, and RNA Loading techniques such as techniques based on electroporation, virus infection of the secreting cells, and targeted embedding of specific RNA sequences via sequence- recognition domains fused to vesicular proteins.” This encompasses both naturally occurring and synthetic exosomes which are “enriched” by either separation methods or methods of adding miRNA into the cell.
The combined teachings of Sahoo, Sahoo2, Salomon , and King render obvious the composition of claim 1. Moreover, Sahoo teaches that the exosomes express and are enriched for hsa-miR-146b-5p as the miRNA is increased in the exosomes via filtration and separation techniques (p. 22, Table 2, 2nd column, para. 0078, 0157; Table 1). As the same method steps are utilized as the present invention (Thery (2006); IDS Reference) (para. 0067), it is inherent that the same results would additionally occur in the enrichment of specific miRNAs. Additionally, Sahoo teaches that exogenous miRNA can be loaded into the exosomes (para. 0079).
It would have been obvious at the time of the effective filing date to further load desired exogenous miRNA into the exosomes as it is a known process in the art to deliver target miRNA, thereby increasing the miRNA concentration within the exosomes.
Regarding claims 11, The combined teachings of Sahoo, Sahoo2, Salomon , and King render obvious the composition of claim 1. Moreover, Sahoo teaches that the vesicles contain CD34 protein (para. 0009).
Regarding claims 12-15, The combined teachings of Sahoo, Sahoo2, Salomon , and King render obvious the composition of claim 1. Moreover, as Sahoo obtains the exosomes through the same method of Thery (2006; IDS Reference) (para. 0067) as the instant invention (Specification, Example 1), the same amount of exosomal concentration within the composition would be isolated as the same method steps yield the same results.
Regarding claims 16-17, The combined teachings of Sahoo, Sahoo2, Salomon , and King render obvious the composition of claim 1. Moreover, Sahoo teaches that the pharmaceutical composition combines the exosomes with a carrier for use (para. 0059). Exosomes were purified and resuspended in PBS for use (i.e. a liquid, suspension) (para. 0093).
Regarding claim 26, and the limitation where the suitable culture medium does not contain FBS, Sahoo teaches that the MNCs were cultured in X-VIVO 10 serum-free cell-culture medium (Lonza Group Ltd, Basel, Switzerland) containing 0.25% human serum albumin and supplemented with 100 ng/ml Flt-3L, 100 ng/ml stem-cell factor, and 20 ng/ml vascular endothelial-growth factor (para. 0091). Therefore the culture medium does not contain FBS.
Regarding claim 27, as each and every method step is provided for in the above combination of references, it would be obvious that the UCBMNCs have the similar amounts of lymphocytes as the cells of the present invention.
Regarding claim 28, The combined teachings of Sahoo, Sahoo2, Salomon , and King render obvious the composition of claim 1. Moreover, Sahoo teaches that a known method of obtaining exosomes is freeze-thaw (i.e. cryopreserved before thawing) (para. 0081).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to subject the UCBMNCs to freeze-thaw conditions as it is a known method of obtaining exosomes from cells and would be substituting or combining the filtration and separation steps of Sahoo with other known alternative methods of obtaining exosomes.
Regarding claims 29 and 30, the combined teachings of Sahoo, Sahoo2, Salomon and King render obvious the composition of claim 1 made by a specific process under hypoxic conditions. As the limitations of these claims are directed towards the morphology and particle size of the resulting exosomes of the specific process which has been made obvious, it is interpreted that these results would additionally be present with a reasonable expectation of success as the same method steps would necessarily yield the same resulting product with a level of predictability.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to Applicant’s arguments and amendments concerning the 103 rejection as previously set forth,
Applicant’s arguments and amendments filed 02/25/2026 have been considered, however they are not persuasive.
First, Applicant argues that the starting material of Sahoo and Ismali is different than the present invention. Applicant states that as previously argued by the reference of Zhang in previous remarks, the secretome of a heterogenous population is not merely the sum of its parts but the result of a complex communication. Applicant further states that Sahoo describes exosomes obtained from CD34+ cells exhibit angiogenic properties whereas mononuclear cells do not. The present invention is exosomes derived from UMBMNCs to accelerate wound healing.
Examiner disagrees. First, Sahoo discloses MNC (which comprises lymphocytes and monocytes) can be isolated from umbilical cord blood. While there is focus on CD34+ cells, the MNCs are also disclosed within the reference. Applicant has not pointed to specific citations from Sahoo. In paragraphs 0041 and 0066, Sahoo discloses that angiogenic miRNA is transferred to MNCs from CD34+ exosomes and that CD34+ exosomes induce angiogenesis. In paragraph 0136, Sahoo does state that MNCs from UCB and their exosomes do not have angiogenic properties in the same manner as CD34+. As Sahoo teaches exosomes obtained from mononuclear cells (MNC) wherein the MNC (which comprises lymphocytes and monocytes) can be isolated from umbilical cord blood, the complex paracrine communication of lymphocytes and monocytes under hypoxic conditions of 0.5% 02, 5% CO2 would have reasonably expected to allows for synergistic signaling between these cells. Applicant’s arguments do not cite specific passages from Sahoo that exclude MNCs. Furthermore, this rejection is based on the combination of references and not merely Sahoo. As stated previously, this specific product which promotes angiogenesis is made by a specific process which is made obvious by the combination of references. Moreover, these claims are directed towards a product not the use of the product.
Applicant further argues that the parameters of the cell culture are a critical metabolic threshold not a variable for routine optimization. Applicant states that their invention shows an unexpected result of an exosomal product with a specific miRNA profile made with the critical parameters being the pre-conditioning regimen of 0.5% oxygen, 5% CO2 and 0% FBS for 18 hours as these miRNA have different, improved characteristics over that of the normoxic conditioned cells resulting in a different population of exosomes without improved properties in wound healing. Specifically, Applicant states that the cells need to be sufficiently stressed to load the five miRNA required for tissue repair, but not stressed to trigger a pathological crisis which is not recognized by the art as 0.5% O2.
Examiner states that there may be unexpected results present, however, the evidence of criticality has not been provided for this hypoxic range over that of other hypoxic conditions provided in the art. See MPEP. For instance, evidence to show that the 1% oxygen hypoxia of Salomon will not result in the same product if applied to the UCBMNCs. This would show that not just hypoxia in general as known in the art, but the specific hypoxic conditions of the present invention, results in the product claimed with improved characteristics. To be in commensurate with the scope of the unexpected results, the specific process must additionally be present, meaning that not merely the oxygen content as claimed in claim 1 is sufficient to be in commensurate with the scope. Applicant specifically points to a pre-conditioning regimen of 0.5% oxygen, 5% CO2 and 0% FBS for 18 hours. No time of conditioning and no FBS content is recited in the claims. There is motivation to optimize as shown in the above rejection.
Applicant further argues that the five miRNA are non-obvious and that the reliance on Ismali is improper as it does not disclose choosing the specific miRNA among the many disclosed which would achieve the wound healing results shown in the specification.
Examiner disagrees. Ismali is utilized first to establish that monocytes can be cultured in hypoxic conditions in order to enhance the miRNA content. Ismali is then utilized as evidence that specific miRNA in monocytes has overlapping miRNA with the present invention which is a heterologous population of lymphocytes and monocytes. Therefore, an artisan would reasonably expect miRNA such as hsa-mir 29b to be present within the composition after the cells are subjected to hypoxic conditions. This establishes that certain miRNAs are inherently present without evidence to the contrary in populations subjected to processes of hypoxia which establishes a reasonable expectation of success to have the five miRNA claimed within the exosomes produced from the MNCs. It is not utilized to “choose” an miRNA but rather provide evidence that miRNA such as the ones claimed inherently exist in exosomes derived from MNC populations. As previously set forth above, the exosomes’ profile of miRNA required in claim 1 is not limited to only hsa-miR-21-5p, hsa-miR-45la, hsa-miR-103a-3p, hsa-miR-29b-3p, and hsa-miR-101-3p, but can include additional hsa-miR as disclosed in claims 8 and 9 (See page 8 of Applicants’ remarks filed 10/24/2025)
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALEXANDRA F CONNORS/ Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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