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 . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
DETAILED FINAL ACTION
Status of Claims
Withdrawn
Cancelled
New
Currently Amended
Previously Presented/Original
Pending
Examined
58 and 68
4, 6, 7, 9, 12, 13, 15, 18, 19, 21, 22, 25-35, 37, 39-49, 51, 52, 54, 56, 59-67 and 69
70
1, 3, 5, 8, 10, 11, 20, 24, 38, 53 and 55
14, 16, 17, 23, 36, 50 and 57
1, 3, 5, 8, 10, 11, 14, 16, 17, 20, 23, 24, 36, 38, 50, 53, 55, 57, 58 and 68
1, 3, 5, 8, 10, 11, 14, 16, 17, 20, 23, 24, 36, 38, 50, 53, 55 and 57
The examined claims are directed to a method.
Status of Previous Objections / Rejections
At this juncture, Examiner withdraws the previous Office action’s (OA) (i.e, 01/14/2026) 35 USC §112 and §103 rejections in view of amendments to the claims, Applicant’s arguments and a reconsideration of the pertinent rejections. However, after careful reconsideration of the claims, Examiner believes 35 USC §103 rejections are appropriate and has applied such rejections to the noted claims.
Response to Amendment
In their reply dated April 14, 2026, Applicant amended the claims to address the rejections and claim interpretations of the prior Office action (OA), to clarify the claim language, and to potentially advance prosecution. In view of the claim amendments and the attendant revised scope of the claimed invention, Applicant’s associated arguments and a careful reconsideration of the claims, Examiner applies new grounds of rejections in this Office Action (OA) and employs a combination of prior art of record and one or more new references.
Claim Objections
Claim 8 is objected to because of the following informality: In item (a), there appears to be an unnecessary comma between ‘acetic’ and ‘acid.’
Appropriate correction is required.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. The inventive entity for a particular application is based on some contribution to at least one of the claims made by each of the named inventors. MPEP §2137.01.
Claims 1, 3, 5, 10, 11, 57 and 70 are rejected under 35 U.S.C. 103 as being unpatentable over Dooley et al. (US20190117792; Dooley)(of record) in view of Wang et al. (US20150065696, Wang) and 3M (Zeta-Plus-Depth-Filters-Brochure; 2020)(of record).
Regarding claims 1, 3, 5, 10, 11, 57 and 70, Dooley discloses a method of preparing purified extracellular vesicles (EVs) from a sample which comprises EVs and one or more impurities (Abstract, [0046], [0095], [0097]), the method comprising
(i) contacting the sample with a depth filter ([0167], where the potential use of a depth filter is noted); and
(ii) collecting a filtrate from the filter ([0093], [0154], [0175], [0203]),
wherein the method reduces one or more impurities of the sample ([0167], [0168], [0187]).
Therefore, Dooley discloses the potential use of a depth filter in the claimed invention, except for the specific type of depth filter, or:
the use of a depth filter selected from a low aluminum (LA) media grade depth filter, a SP media grade depth filter, or both; and
wherein the depth filter comprises cellulose.
Wang is analogous and discloses an apparatus and method for purifying a protein, and involving the use of a capture chromatography resin, a depth filter arranged after the capture chromatography resin, and a mixed-mode chromatography resin arranged after the depth filter (Abstract, [0005]). The depth filter can comprise cellulose ([0031]). One may accomplish the depth filtration with a commercial product such as a 3M Zeta Plus product ([0032]).
3M discloses high performance filter media in its Zeta Plus line, including SP Media with a wide nominal pore size range and LA Media that provides a low level of extractables, including aluminum (page 2). 3M’s Zeta Plus line is referenced by Wang.
Since the only difference between the claimed invention and the prior art is the type of depth filter, when the claimed invention was effectively filed, it would have been obvious to one of ordinary skill in the art to employ an appropriate depth filter and in particular one suitable for the filtered material and the desired outcome, as suggested by Dooley and Wang, including filters with a broad nominal pore size range or ones with low levels of extractables such as aluminum, including filters such as SP Media and LA Media in the 3M Zeta Plus series.
Additional Disclosures Included: Claim 3: The one or more impurities of the EV preparation is decreased compared to one or more impurities of a reference EV preparation,
wherein the reference EV preparation was obtained from a corresponding sample that was not contacted with the depth filter prior to a chromatography,
wherein the one or more impurities of the EV preparation is decreased by at least about 2-fold compared to the reference EV preparation (Examiner interprets the reduction as implicit to the use of the particular media and following the noted steps); Claim 5: In the method, a dynamic binding capacity of a chromatography resin is increased compared to a reference dynamic binding capacity, by at least about 2-fold (Dooley, [0169], [0180], where the increase is considered implicit, or merely the result achieved from carrying out the recited prior steps);
Claim 10: The depth filter has a pore size of less than about 2 µm (Dooley, [0225]; it would have been obvious to choose a suitable pore size); Claim 11: The method of claim 1, wherein:
the filtrate comprises at least about 10% of the EVs present in the sample prior to the contacting,
a turbidity of the filtrate is reduced by at least about 2-fold compared to a reference filtrate that was not contacted with the depth filter, and
the amount of the one or more impurities present in the filtrate is reduced by at least about 2-fold compared to the amount of the one or more impurities present in the sample prior to the contacting with the depth filter (this is viewed as implicit or the result achieved from carrying out the recited prior steps); Claim 57: The EV is an exosome (Dooley, [0009]); and Claim 70: The depth filter is selected from a 60LA depth filter, a 60SP depth filter, or both (3M, page 2, where it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to choose an appropriate filter).
Claims 8, 14, 16, 17, 20, 23, 24, 36, 38, 50, 53 and 55 are rejected under 35 U.S.C. 103 as being unpatentable Dooley et al. (US20190117792) in view of Wang et al. (US20150065696) and 3M (Zeta-Plus-Depth-Filters-Brochure), as applied to claim 1 above, further in view of Woo et al. (US20160114272; Woo) (of record).
Regarding claims 8, 14, 16, 17, 20, 23, 24, 36, 38, 50, 53 and 55, Dooley, Wang and 3M discloses or suggests the method of claim l, except which comprises subjecting the sample to a pre-treatment prior to contacting the sample with the depth filter, wherein the pre-treatment is capable of increasing the filterability of the sample,
wherein the pre-treatment comprises an agent selected from the group consisting of:
an acid selected from acetic, acid, citric acid, carboxylic acid, sialic acid, polyaspartic acid, and polyglutamic acid,
a salt selected from[NH4]2SO4, K2SO4, and KH2PO4,
a cationic polymer selected from chitosan, pDADMAC, and PEI,
an agent selected from an ethylene glycol, a propylene glycol, a polyethylene glycol, a polypropylene glycol, an urea, an arginine-HCl, a lysine, a glycine, a histidine, a calcium, a sodium, a lithium, a potassium, an iodide, a magnesium, an iron, a zinc, a manganese, an aluminum, an ammonium, guanidium polyethylene glycol, a detergent, a chloride, a sulfate, a phosphate, an acetate, a borate, a formate, a perchlorate, a bromine, a nitrate, a dithiothreitol, a beta mercaptoethanol, a tri-n-butyl phosphate, a polyanion, a polyarginine, a polylysine, and a polyhistidine,
a protease inhibitor selected from EDTA and EGTA,
an anti-oxidant selected from cysteine and N-acetyl cysteine, and
a combination thereof.
Woo discloses a depth filtration device for the clarification of biological fluids including a composite depth filter media having a nonwoven first layer integral with a second layer containing a polyaeryionitrile (PAN) fibers, a filter aid, and a wet-strength resin, where the depth filter media exhibits increased creased binding capacity for soluble impurities (Abstract). In some cases, high levels of aluminum ions in the final product can have a neurotoxic effect on the human nervous system ([0007]). Woo’s device avoids extensive preflushing needs and release of organic, inorganic and bioburden extractables by providing a depth filter media having a reduced amount of extractables in the filters, thereby reducing the amount of water required for pre-use flushing, and exhibits an increased binding capacity for host cell proteins and other soluble impurities within a cell culture/biological feedstream during a flow through adsorption process for harvested cell culture fluids ([0017]). Woo refers to the traditional use of cellulose with diatomaceous earth and resin and a preference for certain synthetic polymers ([0006], [0007], [0064]). Woo notes the potential to pretreat with acid ([0012].
When the claimed invention was effectively filed, it would have been obvious to one of ordinary skill in the art to pretreat prior to contacting the sample with the depth filter, wherein the pre-treatment is capable of increasing the filterability of the sample and wherein one can routinely experiment with alternate substances to choose a suitable pretreatment substance.
Additional Disclosures Included: Claim 14: The one or more impurities comprise a nucleic acid molecule, a protein, or both, and wherein the nucleic acid molecule and the protein are not associated with the EVs (Wang, [0003]; Woo, [0002]); Claim 16: The one or more impurities comprise a histone aggregate, a scaffold moiety aggregate, a beta-actin binding protein, or any combination thereof (Woo, [0002], [0016]); Claim 17: The method further comprising (iii) contacting the filtrate with a chromatography resin (Woo, [0043]),
wherein the contacting results in one or more EVs of the filtrate to attach to the chromatography resin, wherein the chromatography resin comprises a cation exchange (CEX) chromatography resin, an anion exchange (AEX) chromatography resin, a mixed mode chromatography (MMC) resin, an affinity chromatography resin, a pseudo affinity chromatography resin, a hydrophobic interaction resin, a hydrophobic charge induction resin, an immobilized metal affinity resin, a ceramic hydroxyapatite resin, a fluoro hydroxyapatite resin, or any combination thereof (Woo, [0043]); Claim 20: The filtrate is contacted with the chromatography resin in a loading buffer, which comprises a salt selected from the group consisting of NaCl, KCI, PO4, CaCl2, MgCl2, Mg2SO4, ZnCl2, MnCl2, MnSO4, NaSCN, KSCN, LiCI, NaPO4, K2HPO4, Na2SO4, K2SO4, NaAcetate, sodium bromide, lithium chloride, sodium iodide, potassium bromide, lithium bromide, sodium fluoride, potassium fluoride, lithium fluoride, lithium iodide, sodium acetate, potassium acetate, lithium acetate, potassium iodide, calcium sulfate, sodium sulfate, chromium trichloride, chromium sulfate, sodium citrate, iron (III) chloride, yttrium (III) chloride, potassium phosphate, potassium sulfate, sodium phosphate, ferrous chloride, calcium citrate, magnesium phosphate, ferric chloride, arginine-HCI, and any combination thereof (Woo, [0043], [0104]); Claim 23: The method further comprises (iv) contacting the chromatography resin with a wash buffer, wherein (iv) occurs after (iii) (Woo, [0104]; Dooley, [0153]-[0158]); Claim 24: The wash buffer comprises:
(a) a nuclease, wherein the nuclease comprises an endonuclease, exonuclease, or both, wherein the endonuclease comprises a salt active nuclease (SAN), Benzonase, Denarase, Kryptonase, or any combination thereof;
(b) a cation, wherein the cation comprises a monovalent cation, a divalent cation, or both;
(c) an anion;
(d) an excipient, wherein the excipient is selected from the group consisting of:
(i) an acid selected from acetic, acid, citric acid, carboxylic acid, sialic acid, polyaspartic -acid, and polyglutamic acid,
(ii) a salt selected from [NH4]2SO4, K2SO4, and KH2P04,
(iii) a cationic polymer selected from chitosan, pDADMAC, and PEI,
(iv) an excipient selected from an ethylene glycol, a propylene glycol, a polyethylene glycol, a polypropylene glycol, an urea, an arginine-HCl, a lysine, a glycine, a histidine, a calcium, a sodium, a lithium, a potassium, an iodide, a magnesium, an iron, a zinc, a manganese, an aluminum, an ammonium, guanidium polyethylene glycol, a detergent, a chloride, a sulfate, a phosphate, an acetate, a borate, a formate, a perchlorate, a bromine, a nitrate, a dithiothreitol, a beta mercaptoethanol, a tri-n-butyl phosphate, a polyanion, a polyarginine, a polylysine, and a polyhistidine,
(v) a protease inhibitor selected from EDTA and EGTA,
(vi) an anti-oxidant selected from cysteine and N-acetyl cysteine, and
(vii) a combination thereof; or
(e) any combination of (a) to (d); and
wherein the chromatography resin is contacted with the wash buffer at least 2 times (Dooley, [0153], [0158], where it would have been obvious to employ an appropriate wash buffer); Claim 36: The method further comprises (v) contacting the chromatography resin with an elution buffer (Dooley, [0158]),
wherein (v) occurs after (iv),
wherein the contacting of the chromatography resin with the elution buffer releases one or more of the attached EVs from the chromatography resin (Dooley, [0158]; in view of the limited choices, it would have been obvious to one of ordinary skill in the art to experiment with the order of application to achieve a predicable solution and a reasonable expectation of success); Claim 38: The method further comprises (vi) collecting an eluent after (v),
wherein the eluent comprises EVs, wherein a concentration of the EVs present in the eluent is increased by at least about 2-fold compared to a reference concentration,
wherein a mean particle size of the eluent is reduced by at least about 2-fold compared to a reference mean particle, wherein the mean particle size of the eluent is between about 20 nm to about 300 nm, and
wherein a polydispersity index of the eluent is reduced by at least about 10%, compared to a reference polydispersity index (claim 36 analysis; the results are considered implicit, or the results achieved from carrying out the previously recited prior steps); Claim 50: The method further comprises contacting the eluent with one or more additional chromatography resins,
wherein the one or more additional chromatography resins comprise an anion exchange chromatography (AEX) resin, a cation exchange chromatography (CEX) resin, a mixed mode chromatography (MMC) resin, a hydrophobic charge induction chromatography resin, an immobilized metal affinity resin, an affinity resin, a pseudo affinity resin, a hydrophobic interaction chromatography resin, or any combination thereof (Dooley, [0169], [0180]); Claim 53: The method comprises a first chromatography step
wherein the first chromatography step comprises contacting the filtrate with a AEX chromatography resin,
wherein the second chromatography step comprises contacting the eluent from the first chromatography step with a MMC chromatography resin, and
wherein the third chromatography step comprises contacting the eluent from the second chromatography step with an additional MMC chromatography resin (Woo, [0043], [0045], where it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ suitable chromatography resins for the desired purpose); and Claim 55: The sample is contacted with the chromatography resin and/or the additional chromatography resin at least two times and
wherein the sample is contacted with:
a. an AEX resin;
b. a CEX resin;
c. a MMC resin;
d. an affinity chromatography resin;
e. a HIC resin;
f. a ceramic hydroxyapatite resin;
g. an IMAC resin;
h. a HCIC resin; or
i. any combination thereof (Dooley, [0180]; Woo, [0043], [0078]; where it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to contact the sample an appropriate number of times with a suitable resin, or combination of resins).
Response to Arguments
Applicant’s arguments filed 04-14-2016 have been fully considered. In view of the claim amendments, Examiner has modified the rejections such that one or more arguments may no longer be applicable.
With respect to Applicant’s teaching away and lack of motivation arguments, Examiner disagrees. While Woo indicates a preference for certain non-cellulose options, with certain advantages, Woo also admits that cellulose is a traditional choice that one can readily employ ([0200]). Therefore, Woo does not teach away. Nevertheless, Examiner did not apply Woo as a primary reference thereby further obviating Applicant’s teaching away argument.
With respect to the 3M brochure and the use of the Zeta Plus filters, although the brochure does not specifically mention the filtration of extracellular vesicles (EVs), the brochure become more relevant in that certain analogous prior art (e.g., Wang) specifically mentions these type of depth filters. Thus, these 3M filters are clearly amenable and suitable for filtering EVs.
With respect to the amended claims, Examiner has added a new reference and additional rationales with respect to any new or added/amended limitations. As such, Examiner believes all claim limitations as well as each of Applicant’s relevant arguments are fully and properly addressed either in this section or in the modified patentability analysis above.
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.
Electronic Inquiries
Any inquiry concerning this communication or an earlier communications from the examiner should be directed to Hayden Brewster whose telephone number is (571) 270-1065. The examiner can normally be reached M-Th 9 AM - 4 PM.
Alternatively, to contact the examiner, Applicant may send a communication, via e-mail or fax. Examiner’s direct fax number is: (571) 270-2065. Examiner's official e-mail address is: "Hayden.Brewster@uspto.gov." However, since e-mail communication may not be secure, Examiner will not respond to a substantive e-mail unless Applicant’s communication is in accordance with the provisions of MPEP §502.03 & related sections that discuss the required Authorization for Internet Communication (AIC). Nonetheless, all substantive communications will be made of record in Applicant’s file.
To facilitate the Internet communication authorization process, Applicant may file an appropriate letter, or may complete the USPTO SB439 fillable form available at https://www.uspto.gov/sites/default/files/documents/sb0439.pdf, preferably in advance of any substantive e-mail communication. Since one may use an electronic signature with this particular form, Applicant is encouraged to file this form via the Office’s system for electronic filing of patent correspondence (i.e., the electronic filing system (Patent Center)). Otherwise, a handwritten signature is required. In addition to Patent Center, Applicant can submit their Internet authorization request via US Postal Service, USPTO Customer Service Window, or Central Fax. Examiner can also provide a one-time oral authorization, but this will only apply to video conferencing. It is improper to request Internet Authorization via e-mail.
Examiner interviews are available via telephone, in-person, and via video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) form available at http://www.uspto.gov/interviewpractice, or Applicant may call Examiner, if preferable. Applicant can access a general list of patent application forms at either https://www.uspto.gov/patent/forms/forms-patent-applications-filed-or-after-september-16-2012 (applications filed on or after September 16, 2012) or https://www.uspto.gov/patent/forms/forms (applications filed before September 16, 2012). Note that the language in an AIR form is not a substitute for the requirements of an AIC, where appropriate. The mere filing of an Applicant Initiated Interview Request Form (PTOL-413A) or a Letter Requesting Interview with Examiner, in EFS-Web, may not apprise Examiner of such a request in a timely manner.
If attempts to reach the Examiner are unsuccessful, Applicant may reach Examiner’s supervisor, Bobby Ramdhanie at 571-270-3240. The central fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HAYDEN BREWSTER/Examiner, AU 1779
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