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 .
Status of the Claims
Claims 17 and 18 are new. Claims 1-18 are pending. Claims 6-11 are withdrawn. Claims 1-5 and 12-18 are under examination.
Priority
This application is a national stage entry of PCT/IB2022/059983 filed on 10/18/2022, which claims priority from CH070433/2021 filed on 10/22/2021 and IT102021000027167 filed on 10/22/2021.
Objection/Rejection Withdrawn
The objections over claim 1 from the previous action are withdrawn, although a new objection is needed due to an amendment that made an issue with the lettering of one of the deleted steps.
The objection over claims 2, 14 and 15 is withdrawn per applicant’s amendment to the claims.
The objection over claim 5 is withdrawn per addition of the comma.
The objection over claim 16 is withdrawn per applicant’s amendment.
The rejection under USC 112(b) over claim 1 is withdrawn per applicant’s amendment to remove the optionally steps within the middle steps b) and f).
The rejection under USC 112(b) over claim 1 for “traditionally known filtration or decantation” is withdrawn per applicant’s deletion of this phrase.
The rejection under USC 112(b) over claim 1 for “a pre-defined temperature and time” is withdrawn per applicant’s removal of “pre-defined” from the claim.
The rejection under USC 112(b) over claims 1 and 4 for “at least one ultrafiltration and concentration steps” is withdrawn per applicant’s amendment to remove “at least one”.
The rejection under USC 112(b) over claim 1 for “defined pore-sizes and ionic strength” is withdrawn per applicant’s deletion of “defined”.
The rejection under USC 112(b) over “adjusted water or buffer” is withdrawn per applicant’s amendment to delete “adjusted” from the phrase.
The rejection under USC 112(b) over “filtration/clarification” is withdrawn per applicant’s amendment to provide “second filtration or clarification”.
The rejection under USC 112(b) over “standard sterile filters” is withdrawn per applicant’s amendment to remove “standard”.
The rejection under USC 112(b) over “at least tens of minutes” is withdrawn as the applicant amended to provide “at least ten minutes”.
The rejections under USC 112(b) corresponding to those above where dependent claims were rejected as being dependent on the indefinite claims are also withdrawn.
The rejection under USC 103 over Bolen WO2020010161A1 (1-9-2020), Nordin et al (Nanomedicine: Nanotechnology, Biology and Medicine, May 2015, volume 11, pages 879-883) and Wijenayake et al is withdrawn per applicant’s arguments, namely those involving Nordin as it only sees utility for simple matrices where milk is complex.
The rejection under USC 103 for claim 5 over Bolen WO2020010161A1 (1-9-2020), Nordin et al (Nanomedicine: Nanotechnology, Biology and Medicine, May 2015, volume 11, pages 879-883), Wijenayake et al (bioRxiv, August 14, 2020, doi: https://doi.org/10.1101/2020.08.14.251629) and Kusuma et al is withdrawn per applicant’s arguments.
As these rejections are withdrawn, applicant’s arguments toward these rejections are now moot.
New Objection – Due to Applicant’s Amendment
Claim Objections
Claim 1 is objected to for item e) as it is a step that has been completely deleted by the applicant. The “e)” here appears to be a remnant. Thus, item f) should actually be e) and item g) should be f). Dependent claims would have to be corrected as needed.
Appropriate correction is required.
New Rejections under USC 112(b) – Due to Applicant’s Amendments
Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5 and 12-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "said cleared milk" in the claim without a recitation of a step that would make cleared milk or “a cleared milk”. There is insufficient antecedent basis for this limitation in the claim. It appears this happened when amending the claim for former step b).
Claims 2-5 and 12-18 are rejected as being dependent on an indefinite claim.
Claim 1 recites the limitation "said stabilized EVs concentrated preparation" in the claim without a recitation of a step that would make stabilized EVs concentrated preparation or “a stabilized EVs concentrated preparation”. There is insufficient antecedent basis for this limitation in the claim. It appears this happened when amending the claim for former step f).
Claims 2-5 and 12-18 are rejected as being dependent on an indefinite claim.
Claim 18 (new claim) is indefinite for step (e) as it appears there is no longer a step e) in claim 1. Limitation of step e) was completely deleted and it appears to jump from step d) to step f).
Maintained Rejection – Modified As Necessitated by Amendment/New Claims
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries 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.
Claims 1-5, and 12-18 are rejected under 35 U.S.C. 103 as being unpatentable over Bolen WO2020010161A1 (1-9-2020) and Patel US 10729156 B2 as evidenced by Hasegawa et al (FEMS Microbiology Letters, 2003, volume 223, pages 41-46).
As the process uses “comprises” as the transition phrase, it is open to other steps and elements of the prior in addition to what is in the claims.
Each step beginning with “optionally” will be read as being optional.
Bolen teaches milk vesicles such as exosomes and other vesicles (pages 11-27). Bolen teaches purification of exosomes/vesicles (examples 1 and 5 in Bolen), and thus, recognizes this goal of its methods. The basic process of Bolen is “In some embodiments, the method for preparing a composition comprising milk vesicles may comprise: (i) providing a first milk sample; (ii) removing casein and/or lactoglobulin from the first milk sample to produce a second milk sample; and (iii) isolating milk vesicles from the second milk sample to produce a composition comprising the milk vesicles” (page 7). Bolen teaches that milk can be processed with a combination of one or more of homogenization, pasteurization, sterilization and/or irradiation (page 16). Bolen teaches casein removal with enzymes capable of coagulating or digesting casein, for example, using rennet (a mixture of enzymes capable of curdling milk) (page 93). Bolen teaches rennet includes the enzyme, chymosin and optionally other enzymes like pepsin (page 93). Example 4 of Bolen teaches preparation of milk vesicles involving casein removal via coagulation with vegetable rennet (page 104). Bolen offers reasoning to remove/eliminate caseins with sizes of 25-30 kDa and/or lactoglobulins of sizes 10-20kDa (page 93). Bolen teaches enrichment of the milk vesicles by tangential flow filtration (page 94). Bolen teaches modifications to milk vesicles may be subject to extrusion (once or multiple times) through a filter with suitable size (e.g. 50 nM, 75 nM or 100 nM) to change size distribution (page 27). The layer in the filter with pores is the membrane (as evidenced by Hasegawa that shows such filters have porous membranes, abstract and introduction of Hasegawa). Bolen teaches “In some embodiments, a filter such as a 0.2 micron filter is used to remove larger debris from solution. In some embodiments, the method for separation of milk vesicle (for example, in the 80-120 nanometer range) includes separation based on specific milk vesicle properties such as size, charge, density, morphology, protein content, lipid content, or epitopes recognized by antibodies on an immobilized surface (immune-isolation)” (pages 90 and 91). On page 91, Bolen allows for ultracentrifugation as a further technique of separation and allows for size exclusion based on different filters such as 0.45 micron or 0.22 micron filters. Bolen teaches buffer substances such as potassium sorbate to make pharmaceutical compositions (bottom of page 73). Bolen teaches methods for homogenization, pasteurization, sterilization and irradiation of milk are known in the art (page 16, lines 22-32). Bolen allows for different pasteurization processes and indicates that pasteurization is heating up milk and then quickly cooling it to eliminate certain bacteria (page 16, lines 9-15). Bolen teaches milk vesicles being stable at 60-80 C for 30 minutes (page 23, lines 28-30). Thus, Bolen provides for providing milk (a sample of milk) in step a, optional filtration process of step b due to its teachings of filtration as a separation technique and reasons for filtering, subjecting the milk to an enzyme mix for coagulation of milk protein(s) to obtain liquid with coagulated protein(s) of step c, separating coagulated proteins with at least one filter (where filters have porous layers) in step d since it is recognized as a suitable separation technique, separations based on other factors such as size, charge (relates to ionic states) and density that would partially provide step e, adding agents like potassium sorbate (step f) (buffering substance in Bolen, page 73) to form a pharmaceutical composition and teachings of pH adjusted compositions that promotes adjusting pH (bottom of page 75) (also step f), subjecting the composition to a second filtration/clarification step by teachings of possible multiple filtrations/separations in Bolen (step g) and using sterile filtration with filters of pore sizes less than one micron (optional step h). As Bolen teaches filtrations, enzyme treatment to remove casein, and separations of the milk in a process to obtain the exosomes/vesicles, there is an expectation of the liquid becoming clearer/more transparent with each separation.
Bolen does not teach a heating step after the enzyme coagulation step and temperatures of this step in dependent claims. Bolen does not teach ultrafiltration, but allows for filtration and various separation techniques in its processes.
Patel teaches methods of purifying exosomes from whey (separated from a milk product) (abstract). Patel teaches ultrafiltration for its process (abstract). Patel teaches optionally drying to form a powder after isolating the exosomes (abstract). Drying to form a powder is lyophilization. Patel teaches enzymatic coagulation may be used and rennet may be used for the enzymes (column 5, lines 22-30). Patel teaches temperatures after the first ultrafiltration or second ultrafiltration may be raised to about 55 degrees C (column 6, lines 55-60 or column 7, lines 40-42). Patel teaches membranes configured to retain molecules greater than about 10 kda or greater than 100 kda (column 2). Patel provides the drying involves spray drying (column 2, lines 25-30). Patel teaches a freeze-dried powder (column 9, lines 8-12).
One of ordinary skill in the art before the time of filing would have included an ultrafiltration step as well as heated to temperatures including 55 degrees C between steps in an exosome isolation procedure by the combined teachings of the prior art. As both Bolen and Patel are to the making of exosomes from milk, one of ordinary skill in the art would utilize the steps of filtration and ultrafiltration, enzyme coagulation, heating and spray drying/freeze drying to make purified milk exosome products as these are seen as steps used in methods of isolating exosomes from milk products. There would be a reasonable expectation of success in achieving better purified exosomes by combining isolation/purification steps of the prior art known for such a purpose. One of ordinary skill in the art by the teachings of Bolen and Patel that teach filtrations/ultrafiltration would have adjusted pore size of filters or size exclusions and how many filtrations were performed based on the materials to be excluded from or maintained with the exosome preparations with a reasonable expectation of obtaining purified milk exosomes of appropriate sizes for therapeutic purposes.
Response to Applicant’s Arguments
Applicant argues the rejection under USC 103 over Bolen and Patel as evidenced by Hasegawa. Applicant argues that the heating step is performed prior to the ultrafiltration steps in step b’ of claim 1 and that Wauben (a reference brought in by applicant) was prior art that would discourage/teach away from combining Bolen with teachings of Patel. Applicant also argues the specific sequence of steps yields highly unexpected matrix-altering synergies that enable scalability without membrane fouling. In regard to the teachings of Wauben, this is not a reference used in the rejections of record. The rejections are based on the prior art cited by the examiner with Bolen teachings many of the steps of applicant’s claims and Patel teaching a heating step and ultrafiltration that is used for isolating extracellular vesicles from a milk product. Hasegawa is an evidentiary reference to provide that filters are porous membranes, where filters are provided by Bolen’s teachings. In a rejection under USC 103, it is the combination of the references with motivations of the references that teaches the claimed invention. Even when Patel provides for heating after a first or second ultrafiltration, currently nothing in the claims prevents an ultrafiltration step from occurring before the heating step as the claims use “comprising” as a transition phrase. Note the milk in the applicant’s claims may be cleared milk (which can result from a filtration process). Even if applicant amends to exclude ultrafiltration from being done before step b’, applicant’s argument that this particular sequence of steps is important is not argued in a manner to explain why the placement of the heating (thermal treatment) step is critical and why ultrafiltration is critically performed only after the thermal treatment. As of now, the teachings of Bolen and Patel provide for the steps, materials and treatment conditions of applicant’s claims and one of ordinary skill in the art would routinely make adjustments and optimizations in the processes with such prior art steps, materials and conditions to produce other methods of isolating purified milk EVs with the reasonable expectation of success in isolating milk EVs, which is the goal of both Bolen and Patel.
For this reason, this rejection is maintained.
Conclusions
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARK V STEVENS whose telephone number is (571)270-7080. The examiner can normally be reached M-F 9:00 am to 6:00 pm EST.
Examiner interviews are available via telephone, in-person, and 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) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian-Yong Kwon can be reached at (571)272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MARK V STEVENS/Primary Examiner, Art Unit 1613
