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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04 March 2026 has been entered.
Status of the Claims
Applicant’s submission filed 04 March 2026 has been entered. Claims 1, 3-4, 6, 10, 12-15, 18, 23, 26-27, 44, and 49-51 are pending. No claim has been amended, cancelled without prejudice or disclaimer, or newly added. Therefore, prosecution on the merits continues for claims 1, 3-4, 6, 10, 12-15, 18, 23, 26-27, 44, and 49-51. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1, 3-4, 6, 10, 44, and 49-51 under 35 USC 103 over Zhang et al in view of Maggini et al
Applicant has traversed the rejection, asserting in Pages 5-6 of the Remarks filed 04 March 2026 that Zhang et al disclose the manipulation of monocytes while Maggini et al disclose the manipulation of macrophages, wherein monocytes and macrophages are distinct cell types. Applicant furthers this assertion, stating that neither Zhang et al nor Maggini et al teach or suggest marker expression of a regulatory phenotype in a monocyte, and that marker phenotype alone does not establish phenotypic equivalence. In response, although the Examiner contends that there are parallels between monocytes and macrophages, Applicant’s arguments have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Therefore, the rejection of record is withdrawn.
RE: Rejection of claims 12, 14-15, 18, 23, and 26 under 35 USC 103 over Hematti et al in view of Zhang et al as evidenced by Rőszer
Applicant has traversed the rejection, asserting in Pages 6-7 of the Remarks filed 04 March 2026 that neither Hematti et al, Zhang et al, nor Rőszer disclose regulatory monocytes. Applicant furthers this assertion, stating that marker phenotype alone does not establish phenotypic equivalence. In response, although the Examiner contends that there are parallels between monocytes and macrophages, Applicant’s arguments have been fully considered and are persuasive. However, upon further consideration, a new ground of rejection is made in view of Hematti et al in view of Varga et al (Mol Cell Pediatr, 2018).
Therefore, the rejection of record is withdrawn.
RE: Rejection of claims 12, 14-15, 18, 23, and 26-27 under 35 USC 103 over Hematti et al in view of Zhang et al as evidenced by Rőszer, and further in view of Gelblum et al
Applicant has traversed the rejection, asserting in Page 7 of the Remarks filed 04 March 2026 that neither Hematti et al, Zhang et al, Rőszer, nor Gelblum et al disclose regulatory monocytes. Applicant furthers this assertion, stating that marker phenotype alone does not establish phenotypic equivalence. In response, although the Examiner contends that there are parallels between monocytes and macrophages, Applicant’s arguments have been fully considered and are persuasive. However, upon further consideration, a new ground of rejection is made in view of Hematti et al in view of Varga et al (Mol Cell Pediatr, 2018).
Therefore, the rejection of record is withdrawn.
RE: Rejection of claim 13 under 35 USC 103 over Hematti et al in view of Hematti ‘042
Applicant's arguments filed 04 March 2026 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting on Page 8 of the Remarks filed 04 March 2026 that Hematti ‘042 does not disclose or suggest administering a monocyte to treat an autoimmune disease. In response, the Examiner respectfully submits that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Hematti ‘042 is a secondary reference utilized to teach that MSC-educated macrophages – which are monocytes that are isolated from PBMCs and treated with MSCs – are administered to treat an autoimmune disease (Paragraphs [0024], [0032], [0039], [0041]-[0042], [0073]). Therefore, the ordinary artisan would have recognized that the monocytes of Hematti et al can also be utilized as an autoimmune therapeutic.
Applicant has further traversed the rejection, asserting in Page 8 of the Remarks filed 04 March 2026 that the combination of Hematti et al and Hematti ‘042 fail to teach regulatory monocytes. In response, the Examiner respectfully submits that independent claim 13 does not require the monocyte to have a regulatory phenotype, and instead only requires the monocyte to be treated with an isolated MSC exosome prior to being administered to a subject.
Therefore, the rejection of record is maintained.
New/Maintained Grounds of Rejection
Claims 1, 3-4, 6, 10, 12, 14-15, 18, 23, 26, 44, and 49-51 are rejected under 35 U.S.C. 103 as being unpatentable over Hematti et al (2019/0249144 A1, of record) in view of Varga et al (Mol Cell Pediatr, 2018).
Hematti et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 12 February 2018. Varga et al is considered prior art under 35 USC 102(a)(1), with a publication date of 03 April 2018.
Regarding claims 1 and 44: Hematti et al disclose an ex vivo generated population of educated monocytes specific to lipopolysaccharide (LPS), as well as methods of making and using such monocytes (Abstract, Paragraph [0007]).
As such, Hematti et al disclose that an extracellular vesicle is first isolated from a mesenchymal stem cell (MSC) previously exposed to LPS, and then co-cultured in vitro with a CD14+ monocyte until the CD14+ monocyte acquires an immunosuppressive, reparative, anti-inflammatory phenotype (Paragraphs [0007], [0010], [0018], [0052]; Figure 4). With that, Hematti et al disclose that the generated anti-inflammatory CD14+ monocytes show a significant decrease in expression of CD16, and are characterized by having a nominal percentage of CD14+CD16+ monocytes (Paragraphs [0018], [0051]-[0052]; Figure 4).
Hematti et al further disclose that the initial phenotype of the monocyte is CD14+ CD16+, or pro-inflammatory (Paragraphs [0052], [0124]; Page 8 of instant Specification).
Hematti et al do not disclose that the anti-inflammatory CD14+ monocytes are regulatory monocytes, as is required by instant claims 1 and 44.
Varga et al, however, disclose that the phenotype of monocytes can be transitioned from pro-inflammatory to anti-inflammatory in response to different stimuli (Pages 1-3). Varga et al further disclose that the anti-inflammatory monocyte phenotype is synonymous with regulatory monocytes (Pages 1, 3).
Therefore, it would have been prima facie obvious to have modified the method of Hematti et al such that the generated anti-inflammatory CD14+ monocytes are regulatory monocytes, as detailed in Varga et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to transition the pro-inflammatory monocytes into regulatory monocytes, as they contribute to the resolution of inflammatory responses following infection (Varga et al: Page 1), and would have had a reasonable expectation of success given that Hematti et al generate anti-inflammatory CD14+ monocytes that have nominal expression of CD16+. See MPEP § 2143(I)(G). It is also of note that CD14+CD16- expression is indicative of regulatory monocytes. See Page 8 of the instant Specification.
Consequently, Hematti et al as modified by Varga et al render obvious a method of regulating a monocyte phenotype, wherein a pro-inflammatory monocyte is contacted with an isolated MSC exosome such that the pro-inflammatory monocyte is transitioned into a regulatory monocyte. This therefore renders obvious the method (claim 1) and monocyte (claim 44) of the instant claims.
Regarding claim 3: Following the discussion of claim 1, Hematti et al further disclose that the MSC exosome is isolated from MSC-conditioned medium (Paragraphs [0033], [0047]-[0048]). This therefore reads on the method of the instant claim.
Regarding claim 4: Following the discussion of claim 3, Hematti et al further disclose that the MSCs are isolated from bone marrow or adipose tissue (Paragraphs [0004], [0015], [0043], [0081]). This therefore reads on the method of the instant claim.
Regarding claim 6: Following the discussion of claim 1, Hematti et al further disclose that the isolated MSC exosomes are 50-150 nm in diameter (Paragraphs [0015], [0049], [0112]). This therefore reads on the method of the instant claim.
Regarding claim 10: Following the discussion of claim 1, Hematti et al further disclose that the monocyte is co-cultured with the isolated MSC exosome for at least 5 days (Paragraphs [0007], [0010], [0052]). As 5 days is greater than 2 hours, this therefore reads on the method of the instant claim.
Regarding claims 12, 26, 49, and 51: As aforementioned in the discussion of claims 1 and 44, Hematti et al as modified by Varga et al render obvious a method of regulating a monocyte phenotype, wherein a pro-inflammatory monocyte is contacted with an isolated MSC exosome such that the pro-inflammatory monocyte is transitioned into a regulatory monocyte.
Hematti et al further disclose that the isolated MSC exosome-contacted CD14+ monocytes – or educated monocytes – are used to treat or prevent a disease by administering the educated monocytes within a pharmaceutical composition (claims 49, 51) to a subject in need thereof (Paragraphs [0006], [0028], [0064]-[0065]). Hematti et al further disclose that the subjects in need of treatment include those having a condition associated with radiation-induced injury, including radiation-induced cardiac fibrosis (claim 26) (Paragraphs [0055], [0059]). As radiation-induced cardiac fibrosis is a fibrotic disease, this therefore renders obvious the treatment method of instant claim 12 for the same reasons as discussed in the rejection of instant claims 1 and 44.
Regarding claims 14-15: Following the discussion of claim 12, Hematti et al further disclose that the monocytes are isolated from the peripheral blood of the subject (claim 15) prior to being co-cultured with the isolated exosomes (claim 14) (Paragraphs [0024], [0031], [0036], [0080]). This therefore reads on the method of the instant claims.
Regarding claim 18: Following the discussion of claim 12, Hematti et al further disclose that the pharmaceutical composition comprising the educated monocytes is systemically administered to the subject in need thereof (Paragraph [0069]). This therefore reads on the method of the instant claim.
Regarding claims 23 and 50: Following the discussion of claims 12 and 49, Hematti et al further disclose that the pharmaceutical composition further comprises auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired (Paragraphs [0064]-[0065]). This therefore reads on the method (claim 23) and pharmaceutical composition (claim 50) of the instant claims.
Claims 1, 3-4, 6, 10, 12, 14-15, 18, 23, 26-27, 44, and 49-51 are rejected under 35 U.S.C. 103 as being unpatentable over Hematti et al (2019/0249144 A1, of record) in view of Varga et al (Mol Cell Pediatr, 2018), and further in view of Gelblum et al (International Journal of Radiation Oncology*Biology*Physics, 2015, of record).
The discussion of Hematti et al as modified by Varga et al in regards to claim 12 can be observed above and is incorporated herein, the content of which is incorporated in its entirety. Hematti et al as modified by Varga et al render obvious claims 1, 3-4, 6, 10, 12, 14-15, 18, 23, 26, 44, and 49-51. Gelblum et al is considered prior art under 35 USC 102(a)(1).
Regarding claim 27: As aforementioned in the discussion of claim 12 above, Hematti et al as modified by Varga et al render obvious a method of treating a subject suffering from a condition associated with radiation-induced injury comprising administering an effective amount of educated monocytes within a pharmaceutical composition to the subject, wherein the monocytes are educated via the contacting of the monocytes with an isolated MSC exosome prior to being administered to the subject, thereby transitioning the initial pro-inflammatory monocyte into an educated regulatory monocyte.
Hematti et al further disclose that the radiation-induced injury could be from the exposure of the subject to ionizing radiation during a medical procedure, such as radiation therapy to treat lung cancer (Paragraphs [0057], [0059]).
The combination of Hematti et al and Varga et al fail to teach the administration of the educated monocytes for the treatment of pulmonary fibrosis, as required by instant claim 27.
Gelblum et al, however, disclose that non-small cell lung cancer patients treated with external beam radiation therapy develop primary interstitial pulmonary fibrosis (Page E442, 3102, Purpose/Objective(s)).
Therefore, it would have been prima facie obvious to have modified the treatment method of Hematti et al in view of Varga et al to include the administration of the educated monocytes to non-small cell lung cancer patients concurrently suffering from radiation therapy-induced primary interstitial pulmonary fibrosis. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to alleviate the potentially fatal comorbidities associated with radiation therapy, and would have had a reasonable expectation of success based on the disclosure of Gelblum et al (Page E442, 3102, Results) coupled with the protocols outlined in Hematti et al (Paragraphs [0028], [0055], [0059], [0064]) regarding the treatment of patients suffering from radiation-induced injuries. It is also of note that Hematti et al disclose the treatment of patients suffering from lung cancer, which is the same patient population described in Gelblum et al. See MPEP § 2143(I)(G).
Consequently, Hematti et al as modified by Varga et al and Gelblum et al render obvious a method of administering educated monocytes to a subject suffering from radiation-induced pulmonary fibrosis. This therefore renders obvious the method of the instant claim.
Claim 13 remains rejected under 35 U.S.C. 103 as being unpatentable over Hematti et al (US 2019/0249144 A1, of record) in view of Hematti et al (US 2016/0082042 A1, of record, referred to henceforth as Hematti ‘042).
Hematti et al is considered prior art under 35 USC 102(a)(2), with an effective filing date of 12 February 2018. Hematti ‘042 is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claim 13: As aforementioned, Hematti et al disclose isolated MSC exosome-contacted CD14+ monocytes – or educated monocytes – that are used to treat or prevent a disease by administering the educated monocytes within a pharmaceutical composition to a subject in need thereof, wherein the subjects include those suffering from a condition associated with radiation-induced injury (Paragraphs [0007], [0010], [0028], [0052], [0055], [0059], [0064]).
Hematti et al do not disclose the administration of the educated monocytes for the treatment of an autoimmune disease, as is required by instant claim 13.
Hematti ‘042, however, disclose the generation of educated macrophages, wherein mesenchymal stem cells (MSCs) are co-cultured with macrophages to generate mesenchymal stem cell-educated macrophages (MEMs) (Abstract; Paragraphs [0006], [0017], [0031], [0033]). With that, Hematti ‘042 further disclose that, in some cases, the MEMs are obtained by culturing macrophages in the presence of MSC exosomes (Paragraph [0036]).
As such, Hematti ‘042 further disclose that the educated monocytes are administered within a pharmaceutical composition to a subject in need thereof, such as those suffering from radiation-induced cardiac fibrosis or having an autoimmune disease (Paragraphs [0006]-[0007], [0038], [0041]-[0042], [0048]).
Therefore, it would have been prima facie obvious to have modified the treatment method of Hematti et al such that the MSC exosome-treated monocytes are administered to a subject suffering from an autoimmune disease, as detailed in Hematti ‘042. One of ordinary skill before the effective filing date of the invention would have been motivated to broaden the treatment applications of the MSC exosome-treated monocytes, and would have had a reasonable expectation of success since the MEMs of Hematti ‘042 are functionally comparable to the MSC exosome-treated monocytes, which are utilized equally for the treatment of radiation-induced injuries and autoimmune diseases. See MPEP § 2143(I)(G).
Consequently, Hematti et al as modified by Hematti ‘042 render obvious a method of treating an autoimmune disease, wherein an effective amount of a monocyte treated within an MSC exosome is administered to a subject in need thereof. This therefore renders obvious the treatment method of the instant claim.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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/ALYSSA G WESTON/Examiner, Art Unit 1633
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