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 .
DETAILED ACTION
Election/Restrictions
Claims 1-4, 6-8, 10, 12, 14-16, 18, and 20-26 are pending.
Applicant’s election without traverse of Group I, claims 1-4, 6-8, 10, 12, 14-16, 18, and 20-25, in the reply filed on 11/5/25 is acknowledged.
Claim 26 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 11/5/25.
Claims 1-4, 6-8, 10, 12, 14-16, 18, and 20-25 are examined on the merits.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 7, 10, 14, and 20 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by De Miroschedji et al (De Miroschedji et al, Immunomodulatory impact of extracellular-vesicleenriched fractions derived from cell-culture of mesenchymal stem cells. Transfusion Medicine and Hemotherapy, (September 2014) Vol. 41, Supp. SUPPL. 1, pp. 91. Abstract Number: SZT-P09), as evidenced by Wikipedia (graft-versus-host disease from Wikipedia, accessed on 11/7/25, pp 1-12)*.
De Miroschedji et al teach Background: More than 300 NIH registered clinical trials applied mesenchymal stem cells (MSCs) to treat patients with a variety of different diseases e.g. myocardial infarction, stroke and graft-versus-host disease (GvHD). Initially, MSCs were thought to replace lost cells in damaged tissues. Despite controversial reports regarding the outcome of MSC treatments, they rather seem to exert their beneficial effects by the secretion of immunosuppressive factors. In this context small extracellular vesicles (80-140 nm) such as exosomes and microvesicles were identified to mediate the immunosuppressive effects of MSCs. By treating a steroid-refractory (thus claims 3, 4, and 20 are met) GvHD patient (thus either acute or chronic, thus claim 14 is met) with MSC-exosomes (thus a method of treating graft-versus-host disease in a subject, thus intact microvesicles, thus claims 1 and 7 are met), we gained evidence that they can effectively suppress GvHD symptoms. Assuming that MSC-exosomes of different donors differ in their immunosuppressive potential, we aim to harvest MSC EVs from cell-culture supernatants of different donor-derived MSCs and test for their immunomodulatory activities in a T cell proliferation assay. Methods: MSCs are raised from bone marrow aspirates of healthy bone marrow donors (thus claim 10 is met). Their MSC nature is confirmed according to standard criteria (fibroblastic appearance, multi-lineage differentiation potential, cell surface phenotype). MSC-EVs are harvested from MSC-conditioned supernatants by a PEG precipitation (thus polyethylene (PEG) precipitation, thus claim 1 is met) strategy. Nanoparticle tracking analysis (NTA) is used to characterize the particles' concentration and size distribution. Western blot analyses of EV-enriched fractions are performed to detect for the presence of adequate EV-marker proteins such as CD81 and CD63. To determine the immunomodulatory capabilities of given EV preparations, CFSE-stained PBMCs are stimulated with Phytohaemagglutinin (PHA) either in the presence or absence of MSC-EVs. The proliferation kinetics of stimulated PB-MNCs and the expression of T cell activation markers are recorded flow-cytometrically. Results: So far, we have raised MSCs from 20 independent donors (thus claim 2 is met), all fulfilling the criteria of bona fide MSCs and harvested their EVs. NTA analyses revealed the presence of EVs with similar size distributions in all fractions. In our ongoing work, we now characterize the immune modulatory features of the obtained EV fractions in the T cell proliferation assay. Preliminary results indicate different impacts on the proliferation kinetics of PHA stimulated T cells. Currently, we optimize our experimental read-outs to assess impacts of EV-mediated immunosuppression at a more comprehensive level. Conclusion: In good agreement to our hypothesis our preliminary results confirm that EV fractions harvested from supernatants of independent MSCs affect the proliferation of PHA stimulated T cells differently. In our ongoing work we aim to identify MSC-EV fractions with very strong and very weak immunomodulatory activities and compare them at the molecular level comprehensively (see Abstract).
As evidenced by Wikipedia, graft-versus-host disease has symptoms such as weight loss (see page 2).
*This reference is cited merely to relay an intrinsic property and is not used in the basis for rejection per se.
Therefore, the reference is deemed to anticipate the instant claim above.
Claims 1-4, 6-8, 10, 12, 14, 16, and 20-23 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Kordelas et al (Kordelas et al, MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia, (2014 Apr) Vol. 28, No. 4, pp. 970-3) (see IDS filed on 6/11/24), as evidenced by Wikipedia (graft-versus-host disease from Wikipedia, accessed on 11/7/25, pp 1-12)*.
Kordelas et al teach exosomes (thus claim 7 is met) derived from mesenchymal stem cells (MSCs) from bone marrow (thus claim 10 is met) obtained by using PEG 6000 precipitation (thus claim 6 is met), for use in the treatment of therapy-refractory graft-versus-host disease (GVHD) in humans (see whole document).
Kordelas et al teach 35-50% of the patients receiving matched (thus claims 2 and 12 are met) related or unrelated allogenic cell transplantation, develop severe forms of graft-versus host disease (thus claim 14 is met) that cannot be controlled with corticosteroids (thus claims 3, 4, and 20 are met) in up to 50% of GvHD
Kordelas et al teach the average particles sizes are between 99-123 nm (page 971, 2nd column, 1st paragraph) (thus claim 16 is met).
Kordelas et al teach the cutaneous andmucosal GvH showed a remarkable response within two weeks, which as stable even after 4 months following the MSC exosome therapy (thus claim 8 is met), the dosage of the steroids could be reduced from 125 mg/d before to 30 mg/d after the MSC therapy (page 972, 2nd column, 2nd paragraph).
Kordelas et al teach containing lipids, proteins and RNA (thus claim 21 is met), exosomes seem to participate in the intercellular communication processes. Together with the other EVs, exosomes are released from many cell types and can be enriched from virtually all body fluids including blood plasma, urine and slave (page 971, 1st column, 1st paragraph).
Since Kordelas et al teach administrating the claimed intact microvesicles to the claimed subject, it is the underlying mechanism that the administration of intact microvesicles increases Tregs such as FOXP3+ (thus claims 22 and 23 are met).
As evidenced by Wikipedia, graft-versus-host disease has symptoms such as weight loss (see page 2).
*This reference is cited merely to relay an intrinsic property and is not used in the basis for rejection per se.
Therefore, the reference is deemed to anticipate the instant claim above.
Claim Rejections –35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained through the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1-4, 6-8, 10, 12, 14, 16, 18, and 20-25 are rejected under 35 U.S.C. 103(a) as being unpatentable over Kordelas et al and Wikipedia as applied to claims 1-4, 6-8, 10, 12, 14, 16, and 20-23 above, and further in view of Badiavas et al (US 20180104186 A1).
The teachings of Kordelas et al and Wikipedia are set forth above and applied as before.
The teachings of Kordelas et al and Wikipedia do not specifically teach the claimed molecular weight in claim 18, location injection in claim 24, or intravenous delivery in claim 25.
Badiavas et al teach in one embodiment, the washing step removes the precipitating agent. In one embodiment, the microvesicles are washed via centrifugal filtration, using a filtration device with a 100 kDa molecular weight cut off [0148] (thus claim 18 is met) Badiavas et al tach typical preferred compositions are in the form of injectable or infusible solutions. The preferred mode of administration is parenteral (e.g., intravenous (thus claim 25 is met), subcutaneous (thus claim 24 is met) intraocular, intraperitoneal, intramuscular). In a preferred embodiment, the preparation is administered by intravenous infusion or injection. In another preferred embodiment, the preparation is administered by intramuscular or subcutaneous injection [0312] (thus claim 18 is met). Badiavas et al teach in one embodiment, the present invention provides an isolated preparation of microvesicles that is used to diagnose the presence and/or progression of a disease in a patient. In one embodiment, the disease is metastatic melanoma. In an alternative embodiment the disease in an inflammatory/autoimmune disorder such as rheumatoid arthritis. In one embodiment, the disease is graft versus host disease [0037].
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to use the claimed molecular weight of microvesicles, the claimed location or intravenous delivery from Badiavas et al since Badiavas et al teach to do so. Since both of the references teach treating graft versus host disease with isolated microvesicles, one of the ordinary skill in the art would have been motivated to combine the teachings of the references together.
From the teachings of the references, it is apparent that one of the ordinary skills in the art would have had a reasonable expectation of success in producing the claimed invention.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to QIUWEN MI whose telephone number is (571)272-5984. The examiner can normally be reached on Monday-Friday 9:00 am to 5:00 pm.
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/Qiuwen Mi/
Primary Examiner, Art Unit 1655