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 9/18/2025 has been received and entered. Claims 1-6, 8-26, 28-49 and 51-61 are pending.
Election/Restrictions
Applicants previously elected Group I, drawn to a composition comprising purified and enriched population of potent exosomes derived from EVs derived from MSCs. Claims 1-6, 9-24 and 61 read on the elected invention. Claims 25-60 remain withdrawn from consideration, pursuant to 37 CFR 1.142(b), as being directed to non-elected inventions.
Claim Interpretation
For clarity of record the following comments are made of record:
The specification defines “about” as +/- 20% of the numerical value (See ¶00266 of as-filed specification). Therefore the ranges “about 1 mg” and “about 90-100 nm” in claim 1 will be interpreted as “0.8-1.2 mg” and “72-132 nm”, respectively.
The phrase “identity signature [of exosomes]” is interpreted to mean that the exosomes express the recited biomarkers.
The phrase “therapeutic signature [of cargo]” is interpreted to mean that the cargo contains one or more miRNAs.
The phrase “potency signature [of cargo]” is interpreted to mean that the cargo contains one or more of the recited growth factors.
Claim 1 is directed to a composition comprising purified and enriched population of “potent” exosomes derived from MSCs from a specific subset of patients. The term “potent” is understood to mean that the composition has ‘a power or strength or activity’, but does not limit to any particular power or strength or activity.
The exosomes are defined as having the following characteristics: a) express three or more biomarkers selected from CD9, CD63, CD81 and Tsg101. CD9, CD63, CD81 and Tsg101 are proteins common to all exosomes (See Willms et al, Scientific Reports, 2016, Pg 5, 1st paragraph; Novus Biologicals “Exosome Marker Antibodies”, 2025; Jankovicova et al, Int J Mol Sci, 2020, Fig. 1; and instant specification at ¶00629). Therefore, expression of all four biomarkers is considered inherent to exosomes.
b) have a total protein of about 1 mg. Based on the definition of “about”, the claim permits for 0.8-1.2 mg of protein.
c) have a total RNA content greater than 20 µg.
d) have an average size of about 90-100 nm. Based on the definition of “about”, the claim permits for the exosomes to have an average size of 72-132 nm. Per the specification, exosomes have a size range of 40-160 nm, with an average size of 100 nm (See ¶00313). Therefore, the size range is considered inherent to exosomes.
e) contain cargo, said cargo comprising:
(1) one or more miRNAs, the one or more miRNAs being capable of treating an age-related chronic disease characterized by disease-related dysfunction;
(2) one or more of Ang-2, FGF, HGF, IL-8, TIMPO, VEGF, PDGF, and TNFα.
Claims 2-6 define the source of the MSCs from which the exosomes are derived. It is noted that claim 4 states the identity of the MSC is confirmed by expression of a specific combination of surface markers. As the claim is directed to the exosome product, not a method of making, the recitation of a step of confirming the identify of a source MSC is not limiting to the exosome product.
Claim 11 states the composition is formulated for administration by inhalation or for intravenous administration. The claim is interpreted as requiring the composition to be in a physical form that can be administered by inhalation and/or IV. Any liquid, aerosol or powdered formulation will meet this limitation. The claim does not require the composition to actually be administered via those routes.
Claims 13-24 further limit the miRNA cargo in the exosomes. The claims use a combination of physical limitations (e.g. by requiring specific miRNA) and functional limitations (e.g. requiring the miRNA modulate a fibrogenic response to an injury to an organ).
Status of Prior Rejections/Response to Arguments
RE: Objections to claims 1, 12, and 13:
The amendments are effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claims 1-24 under 35 USC 112(b): The amendments to the claims is effective to obviate the previous rejections. It is specifically noted that the amendment to claims 1 and 13-24 now limit the claimed exosomes by defining the cargo contained therewithin by either specific structural and/or functional limitations. The rejections are withdrawn.
RE: Rejection of claims 13-24 under 35 USC 112(a):
As amended claim 13 now recites specific miRNAs that are stated to achieve each of the claimed effects. The rejection, as previously written, is withdrawn.
RE: Rejection of claims 1-24 under 35 USC 102(a)(1) over Whitford et al: Applicants have traversed on the grounds that the MSC-derived exosomes of Whitford et al, despite being from the same cells and harvested via the same process as disclosed in the instant application, do not meet the claim limitations, specifically they do not necessarily contain the required cargo of the instant claims. Applicants assert EV composition is determined not only by the cell type but also by the physiological state of the producer cells (quoting para 0002 of the specification). Applicants assert the exosome cargo is a function of the source cells’ age, gender, estrogen receptor function and status, environmental impact/stressors, donor cell or tissue type, health of the donor organ, organ system, or tissue, and genomics of the donor cell or tissue (quoting para 00243 of the instant specification).
The rejection is withdrawn because Whitford et al does not teach the age of the donors of the MSCs. The claim now requires the MSCs to be from healthy donors 21-40 years of age.
New Grounds of Rejection
Claim Objections
Claim 10 is objected to for a minor informality:
Claim 10 is now the first time the abbreviation “EV” appears in the claim set. It should be preceded by its full term ‘extracellular vesicle’. Correction is required.
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 1-6, 8-24 and 61 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 claim(s) contains 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.
The claims are drawn to exosome compositions having specific cargo (e.g. cargo contains specific miRNA(s) and specific growth factors and/or chemokines). Claim 1 covers a broad scope of exosomes, claims 13-24 recite a variety of specific species of exosomes. The issue at hand is the current disclosure does not support that Applicants were in possession of any species of exosome as claimed.
The instant disclosure details the various miRNA, growth factor and chemokine molecules that are intended to be cargo within the claimed exosomes. The instant disclosure does not show Applicants actually created exosomes with the specific cargo currently claimed. The only disclosure of actually producing exosomes is at paragraph 0061, where ASC-derived exosomes were isolated by Zen-Bio Inc (e.g. the method of Whitford et al). No cargo profile is given for these ASC-derived exosomes. As noted by Applicants in response to the previous rejection over Whitford et al (who produced ASC-derived exosomes), the cargo content of exosomes is deterred not only by the cell type but also by the physiological state of the producer cells, it is a function of the source cells’ age, gender, estrogen receptor function and status, environmental impact/stressors, donor cell or tissue type, health of the donor organ, organ system, or tissue, and genomics of the donor cell or tissue. Therefore it cannot be held that the ASC-derived exosomes necessarily contained the cargo as currently claimed.
Paragraph 00668 discloses a plan for isolating exosomes from bone marrow MSCs from healthy donors aged 21-40 years old and then screening the exosomes to detect a desired miRNA expression profiles. Applicants disclosure amounts to a plan for generating a pool of exosomes that can be screened for potentially having the desired cargo characteristics, and then isolating those exosomes that are identified as having the desired cargo. First, there is no evidence that the starting pool of exosomes would necessarily contain exosomes having the desired cargo. Second, a plan to generate a pool, screen for potential matches, and then isolate matches does not equate to having possession of the actual exosomes having the claimed characteristics.
Overall, it is concluded that Applicants were not in possession of a composition of exosomes as currently claimed. Thus the claims are rejected as failing to comply with the written description requirement.
Claims 1-6, 8-24 and 61 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims are drawn to exosome compositions having specific cargo (e.g. cargo contains specific miRNA(s) and specific growth factors and/or chemokines). Claim 1 covers a broad scope of exosomes, claims 13-24 recite a variety of specific species of exosomes. The issue at hand is the current disclosure does not enable a person having ordinary skill in the art to make the composition(s) without undue experimentation.
As acknowledged by Applicants in the specification, exosome composition and cargo is deterred not only by the cell type but also by the physiological state of the producer cells (See para 0002 of the specification), and is a function of the source cells’ age, gender, estrogen receptor function and status, environmental impact/stressors, donor cell or tissue type, health of the donor organ, organ system, or tissue, and genomics of the donor cell or tissue (See para 00243 of the instant specification). This specificity was also acknowledged by the prior art: Whitford et al (Genetic Engineering & Biotechnology News, 2015) teach that exosomes content is a “fingerprint of the type and status of the cell generating them” (See Pg 1, col. 1, emphasis added). Ludwig et al (Int’l J Mol Sci, 2019) discuss how cell culture conditions, including medium composition, use of serum, growth factors, antibiotics, environmental factors (such as oxygen levels), oxidative stress, temperature and other culture additives can affect exosome levels and cargo composition (See Section 3, Pgs. 4-6). Therefore, exosome cargo is dependent on a variety of factors, including, but not limited to the source cell, as well as the status of the source cell and the culture conditions in which the exosomes were produced.
As the instant application requires exosome compositions with specific cargo molecules, in order to produce the claimed composition, one having ordinary skill in the art must be informed of the appropriate source cell type, status, and cell culture conditions necessary to produce said cargo compositions. However, the specification fails to disclose this necessary information. The only disclosure of actually producing exosomes is at paragraph 0061, where ASC-derived exosomes were isolated by Zen-Bio Inc (e.g. the method of Whitford et al). No cargo profile is given for these ASC-derived exosomes. As noted by Applicants in response to the previous rejection over Whitford et al (who produced ASC-derived exosomes), the cargo content of exosomes is deterred not only by the cell type but also by the physiological state of the producer cells, it is a function of the source cells’ age, gender, estrogen receptor function and status, environmental impact/stressors, donor cell or tissue type, health of the donor organ, organ system, or tissue, and genomics of the donor cell or tissue. Therefore it cannot be held that the ASC-derived exosomes necessarily contained the cargo as currently claimed. Paragraph 00668 discloses a plan for isolating exosomes from bone marrow MSCs from healthy donors aged 21-40 years old and then screening the exosomes to detect a desired miRNA expression profiles. Applicants disclosure amounts to a plan for generating a pool of exosomes that can be screened for potentially having the desired cargo characteristics, and then isolating those exosomes that are identified as having the desired cargo. Instructing a reader to generate a pool, screen for potential matches, and then isolate matches would constitute undue experimentation, as it would require the reader to test a nearly limitless number of cells (even if restricted to bone marrow MSCs, cells from subjects who have lived in different environments would be expected to have MSCs of different statuses and physiological states) and limitless culture conditions.
The absence of any working examples or specific guidance of particular cells and cell culture conditions which would yield exosomes with the particular cargo signatures currently claimed, as well as the art-recognized unpredictability, leads to the conclusion that the instant disclosure does not enable a person of ordinary skill in the art to make the composition as currently claimed.
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