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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/03/2026 has been entered.
Claim 1 has been amended. No claims have been newly added or newly canceled.
Claims 1-2, 4, 6, 8-13 are currently pending.
Claims 10-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 06/13/2024.
Claims 1-2, 4, 6, 8-9 and 13 have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/788545, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The provisional application 62/788545 does not disclose the limitations of “iohexol” or “elutriation” as recited by independent claim 1.
Therefore claims 1-2, 4, 6, 8-9 and 13 have been examined with the effective filing date of PCT/US2020/012359 which is 01/06/2020.
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 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.
Claim(s) 1-2, 4, 6, 8-9 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Guo et al (Theranostics 2017-from IDS filed 07/02/2021) in view of Pages (US 2013/0280342-previously cited), Aatonen et al (Journal of Extracellular Vesicles 2014-previously cited and now further including Supplementary Table 1) and Yon et al (Micromachines, 2018-newly cited).
Regarding claim 1, Guo teach a method of isolating platelet-derived exosomes by extracting PRP from whole blood; isolating platelets from PRP; activating the platelets to induce the release of the exosomes and isolating the exosomes (page 82, column 2, para 6-page 83, column 1, para 2). Filtering of the exosomes to generate filtered, isolated platelet-derived exosomes is also taught (page 83, column 1).
Guo does not describe using elutriation to isolate platelets from PRP or PRP from whole blood.
Pages disclose a system and method for extracting PRP from whole blood and platelets from PRP using a surge elutriation method (pages 1-2 para 9-10, page 3 para 23-24). Pages teach and suggest that their method provides the benefits of a maximum yield, required amount, and numerous advantages over the prior art (page 1 para 5, page 6 para 58).
One of ordinary skill in the art would have been motivated with a reasonable expectation of success to use elutriation to isolate platelets from PRP and PRP from whole blood in the method of Guo because Pages teach and suggest that this method provides the benefits of a maximum yield, required amount, and numerous advantages over the prior art (page 1 para 5, page 6 para 58).
Guo is silent with regard to how the platelets are activated.
Aatonen describe a method of isolating platelet-derived exosomes by extracting platelet-rich plasma (PRP) from whole blood (page 2 column 2); isolating platelets from the PRP (page 2 column 2, last paragraph to page 3 column 1); activating the platelets to induce release of the exosomes by contacting the platelets with thrombin, collagen, and calcium chloride (CaCl2) and isolating the exosomes (page 4 column 1).
Supplementary Table 1 of Aatonen provides evidence that collagen and thrombin activation provides exosomes that comprise PDGF and TGF beta 1 (see pages 5 and 7 of the Supplementary Table 1).
One of ordinary skill in the art would have been motivated to activate the platelets to release the exosomes in Guo by contacting the platelets with thrombin, collagen, LPS, Ca2+ ionophores and/or or calcium chloride (CaCl2) because Aatonen teach that this a suitable way to activate platelets for the release of exosomes. One of ordinary skill in the art would have had a reasonable expectation of success because both Guo and Aatonen are drawn to methods of isolating platelet-derived exosomes.
Providing guidance on instances where the method steps of the prior art and instant claims are the same, Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) states “[T]hat since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims.”
Therefore, while Aatonen is silent with regard to the presence of IGF, and VEGF in their exosomes, since they perform the same steps as claimed the effect of IGF, PDGF, TGF-β1, and VEGF containing exosomes is deemed to be inherently present baring evidence to the contrary.
Regarding the issue of inherency, see Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020). (see MPEP 2112 (IV)).
Therefore, when Guo is modified by the teaching of Aatonen, the modified Guo will also inherently include exosomes that comprise IGF, PDGF, TGF-β1, and VEGF as well.
Guo does not describe using iohexol to isolate their exosomes from their activated platelets.
Yon disclose methods for targeting and isolating exosomes from blood and state that generally the amount of exosomes in the blood is not enough and techniques that increase the yield and purity of exosomes are required (pages 2-3). Density gradient ultracentrifugation is a technique for sorting exosomes from biological samples and is a combination of centrifugation and density gradient media such as iohexol (page 4 section 2.2). This has the advantage of yielding higher purity because the separations are made according to density rather than size. Other advantages include less protein aggregation, less contamination, and good morphological properties (page 4 section 2.2).
Therefore, one of ordinary skill in the art would have been motivated to isolate the exosomes from the activated platelets in the method of Guo by including the combination of centrifugation and iohexol because Yon teach and suggest that generally the amount of exosomes in the blood is not enough and techniques that increase the yield and purity of exosomes are required (pages 2-3). Additional motivation and a reasonable expectation of success are provided because Yon also teach and suggest that the combination of centrifugation and iohexol in the isolation of exosomes provides the advantages of yielding higher purity, less protein aggregation, less contamination, and good morphological properties.
Regarding claims 2, Guo disclose wherein the PRP is extracted from whole blood by centrifuging at 250 x g for 15 minutes (differential centrifugation) at least one time (page 82, column 2, last paragraph – page 83, column 1, first paragraph).
Regarding claim 4, Guo is silent with regard to the number of platelets extracted from PRP.
However, Aatonen describe wherein extracted PRP intended for use in deriving exosomes comprises 250 x 106 platelets/ml (which is at least 2 x 106 platelets per microliter) (page 4 column 1, first paragraph, page 6 Figure 2).
Therefore, one of ordinary skill in the art would have been motivated to extract PRP with about 250 x 106 platelets/ml (which is at least 2 x 106 platelets per microliter) from the PRP in the method of Guo because Aatonen indicate that this is a suitable number of platelets for PRP that is intended for use in the isolation of exosomes. Optimizing the number of platelets in the PRP would allow for the maximal number of exosomes to be produced. One of ordinary skill in the art would have had a reasonable expectation of success because both Guo and Aatonen are drawn to methods of isolating platelet-derived exosomes from PRP.
Regarding claims 6, 9, 13, Guo describe wherein erythrocytes and leukocytes are separated from the platelets (page 83, column 1, first paragraph) and thus the removal of red and white blood cells inherently allows for potential use of the resultant exosomes in the treatment of chronic orthopedic conditions without causing inflammation as well as providing a purified exosome composition that has an at least 1000-fold reduction of these unwanted cells relative to whole blood. The exosome pellet was resuspended in sterile PBS (phosphate buffered saline suitable for use as a pharmaceutical composition) (page 83 column 1, Exosome isolation from PRP). Since the exosomes are intended for therapeutic use (page 81, column 2) optimization of the quantity to arrive at a therapeutically effective amount for any damaged tissue, including joints, would have been a matter of routine optimization and experimentation.
Regarding claims 8, 13, Guo disclose wherein the released exosomes are separated from the platelets by filtration prior to isolation and wherein the exosomes are isolated by centrifugation with a 30% sucrose-D20 cushion and ultra-centrifuged at 100,000 x g for about 70 minutes (page 83, column 1, 2nd paragraph).
Therefore, the combined teachings of Guo et al, Pages, Aatonen et al and Yon et al render obvious Applicant’s invention as claimed.
Response to Arguments
Applicant’s amendments to the claims filed 03/03/2026 have overcome the prior rejections and thus these rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Guo in view of Pages, Aatonen and Yon as described above.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Iwai et al., “Isolation of human salivary extracellular vesicles by iodixanol density gradient ultracentrifugation and their characterizations”, Journal of Extracellular Vesicles, 2016, Vol. 5, pp. 1-17. (see page 14 regarding the use of iohexol in the isolation of extracellular vesicles (EVs))
Kang et al., “Methods to isolate extracellular vesicles for diagnosis”, Micro and Nano Systems Letters (2017) 5:15, pp. 1-11. (see page 4 column 1, regarding the use of iohexol in the isolation of extracellular vesicles (EVs))
De Miroschedji “Human Platelet Lysate Derived Extracellular Vesicles for Use in Medicine”, (US 2019/0290696).
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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