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 .
This application is the national stage entry of PCT/EP2022/066288, filed 15 June 2022; claims benefit of foreign priority document EP 21180184.0, filed 17 June 2021; and claims benefit of foreign priority document EP 21181611.1, filed 24 June 2021. The foreign priority documents are in English.
Claims 17-57 are pending in the current application. Claims 51-57, drawn to non-elected inventions, are withdrawn. Claims 17-50 are examined on the merits herein.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 17-50, in the reply filed on 22 May 2026 is acknowledged.
Claims 51-57 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 22 May 2026.
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.
Claims 17-24, 26, 39-40, 43, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Horlitz et al. (WO 2013/045432 A1, 04 April 2013, provided by Applicant in IDS filed 14 Dec 2023) in view of Tosar et al. (Patel, T., ed., Extracellular RNA: Methods and Protocols, Methods in Molecular Biology, 2018, vol. 1740, p125-137, provided by Applicant in IDS filed 14 Dec 2023).
Horlitz et al. teaches a method for isolating extracellular nucleic acids from a sample by binding the extracellular nucleic acids to a solid phase which carries anion exchange groups, comprising the following steps: binding the extracellular nucleic acids to the solid phase in a binding mixture having a first pH which allows binding the extracellular nucleic acids to the anion exchange groups of the solid phase (abstract). Extracellular nucleic acids have been identified in plasma, serum and other body fluids. Extracellular nucleic acids that are found in respective samples are to a certain extent degradation resistant due to the fact that they are protected from nucleases (e.g. because they are secreted in form of a proteolipid complex, are associated with proteins or are contained in vesicles). The method comprises the following steps: a. binding the extracellular nucleic acids to the solid phase at a first pH which allows binding the extracellular nucleic acids to the anion exchange groups of the solid phase; wherein preferably the sample makes up at least 85% of the volume of the binding mixture; b. separating the solid phase with the bound extracellular nucleic acids; c. optionally washing the extracellular nucleic acids; and d. optionally eluting extracellular nucleic acids from the solid phase (page 5, lines 10-20), addressing limitations of claim 17, 20-22. The respectively concentrated extracellular nucleic acids can then optionally be further purified using a standard nucleic acid isolation protocol (page 9, lines 30-35), addressing limitations of claim 23. The term "extracellular nucleic acids" includes small interfering RNA such as e.g. miRNA and siRNA. In one embodiment, the extracellular nucleic acids are obtained from a body fluid or a sample derived from a body fluid as biological sample such as e.g. blood, plasma, or serum (paragraph spanning pages 10-11), addressing limitations of claims 18 and 48. In one embodiment, the binding mixture is prepared by adjusting the pH of the sample to the first pH. A particularly preferred example of an acidifying solution is an aqueous solution of a sodium acetate/acetic acid buffer, preferably in a concentration of from 0.5 to 5 M, preferably having a pH value in the range of about 2 to about 5, more preferably about 4 (page 12, line 10-30), addressing limitations of claims 39-40, 43, and 48. Horlitz et al. further teaches the nucleic acid binding solid phase treated with a polymer that may be any polymer or polymeric compound as long as it is capable of binding to the nucleic acid binding solid phase (page 36, line 25 to page 37, line 10).
Horlitz et al. does not specifically teach the method for enriching non-vesicular RNA from a cell-free or cell-depleted biological sample that includes non-vesicular RNA (claim 17).
Tosar et al. teaches extracellular vesicles (EVs) are by far the most studied carriers of extracellular small RNAs involved in cell-to-cell communication, most extracellular small RNAs are actually present as soluble vesicle-free supramolecular complexes. Focus on this fraction will increase our understanding on extracellular RNA biology, while serving as a source for biomarker discovery complementary to EVs (page 125, abstract). EVs were initially thought to be the main source of exRNA and the physiological vectors for regulatory RNA exchange between cells. However, stoichiometric analysis has shown that the miRNA content of exosomes is not as high as previously thought. The vast majority of RNase-protected circulating miRNAs in serum was reported to be present in ribonucleoprotein complexes (paragraph spanning page 125-126). Thus, a comprehensive analysis of the extracellular RNA content needs to consider the pool of RNAs not associated with EVs, which seems to be the major reservoir of miRNAs and other small RNA species (page 126, paragraph 2). Tosar et al. teaches methods of preparing the cell-free biological sample from which the non-vesicular extracellular small RNAs are obtained (pages 128-129).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Horlitz et al. in view of Tosar et al. in order to modify the method of Horlitz et al. in order to select the extracellular nucleic acids being isolated to be miRNA from vesicle-free supramolecular complexes. One of ordinary skill in the art would have been motivated to combine Horlitz et al. in view of Tosar et al. with a reasonable expectation of success because both Horlitz et al. and Tosar et al. are drawn to isolation of extracellular nucleic acids, Horlitz et al. teaches these extracellular nucleic acids which can be isolated in the method include both those associated with proteins and those contained in vesicles, and Tosar et al. teaches it is desired to isolate specifically the miRNA from vesicle-free ribonucleoprotein supramolecular complexes, suggesting it would have been obvious to one of ordinary skill in the art to combine Horlitz et al. in view of Tosar et al. in order to isolate the desired non-vesicular extracellular small RNAs.
Claims 25, 27-38, 41-42, 44-47, and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over Horlitz et al. (WO 2013/045432 A1, 04 April 2013, provided by Applicant in IDS filed 14 Dec 2023) in view of Tosar et al. (Patel, T., ed., Extracellular RNA: Methods and Protocols, Methods in Molecular Biology, 2018, vol. 1740, p125-137, provided by Applicant in IDS filed 14 Dec 2023) as applied to claim 17-24, 26, 39-40, 43, and 48 above, and further in view of Filant et al. (Patel, T., ed., Extracellular RNA: Methods and Protocols, Methods in Molecular Biology, 2018, vol. 1740, p43-57, cited in PTO-892).
Horlitz et al. in view of Tosar et al. teach as above. Tosar et al. further teaches a working example of the steps of RNA isolation for the RNA from vesicle-free supramolecular complexes (Tosar et al. page 49). Horlitz et al. further teaches for the elution method generally any suitable elution method can be used. The choice of the second pH value that is suitable for eluting the extracellular nucleic acids from the anion exchange groups inter alia depends on the nature of the anion exchange groups present on the solid phase, the density of the anion exchange groups on the surface of the solid phase and the ionic strength of the elution solution. Suitable pH values for the second pH can be determined by the skilled person (Horlitz et al. page 15, lines 1-10).
Horlitz et al. in view of Tosar et al. does not specifically teach the method further comprises recovering either the non-vesicular RNA and the extracellular vesicles, or the non-vesicular RNA and extracted vesicular RNA from the solid phase (claim 25) or the method for sequentially enriching extracellular vesicles and non-vesicular RNA from a cell-free or cell-depleted biological sample that includes extracellular vesicles and non-vesicular RNA (claim 27).
Filant et al. teaches extracellular RNAs (exRNAs) are initiating increased interest due to their potentials in serving as novel biomarkers, mediators of intercellular communication, and therapeutic applications, and teaches protocols for commercially available kits that have been modified to yield consistent results for isolation of extracellular RNA from both whole serum/plasma and extracellular vesicle-enriched serum/plasma samples (page 43, abstract). Evidence of exRNA in biofluids suggests that they are protected from the environment through association with extracellular vesicles such as exosomes, apoptotic bodies, microvesicles, lipoproteins, and ribonucleoproteins (paragraph spanning pages 43-44). exRNA can be extracted either from whole serum/plasma or from vesicle-enriched serum/plasma. Vesicle enrichment can be done using one of the four methods, namely: precipitation, membrane filtration, affinity purification, and differential centrifugation. ExoRNeasy kit (Qiagen) uses membrane affinity spin columns for binding all types of extracellular vesicles (page 44, paragraphs 2-3). Filant et al. teaches the methods of using the ExoRNeasy kit comprising the isolation of the exosome vesicles followed by the RNA isolation (section 3.4 spanning pages 48-50).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Horlitz et al. in view of Tosar et al. further in view of Filant et al. in order to further modify the method in order to isolate both the extracellular vesicular RNA and the extracellular non-vesicular RNA using separate steps. One of ordinary skill in the art would have been motivated to combine Horlitz et al. in view of Tosar et al. further in view of Filant et al. with a reasonable expectation of success because all of Horlitz et al., Tosar et al., and Filant et al. are drawn to isolation of extracellular nucleic acids., Horlitz et al. and Filant et al. suggest the method is applicable for the isolation of both extracellular vesicular RNA and the extracellular non-vesicular RNA, and Tosar et al. teaches it is desired to separately isolate the extracellular non-vesicular RNA, suggesting it would have been obvious to modify the method in order to isolate both the extracellular vesicular RNA and the extracellular non-vesicular RNA using separate steps. One of ordinary skill in the art would have been motivated to select the optimal reaction conditions for the different steps of isolating the extracellular vesicular RNA and the extracellular non-vesicular RNA from within the broader scope of general conditions taught by Horlitz et al. through routine experimentation because Tosar et al. and Filant et al. suggest different conditions are used for isolating extracellular vesicular RNA and extracellular non-vesicular RNA. See also MPEP 2144.05 at II. providing ““[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”In this case Horlitz et al. teaches the general conditions of the claim, and Tosar et al. and Filant et al. suggest it would have been obvious to one of ordinary skill in the art to perform routine experimentation to discover different optimal conditions for the different RNA isolation steps.
Regarding claim 37, claim 37 depends from claim 36 and recites further limitations of the crowding agent. However, claim 36 recites adding a crowding agent as one of three alternatives, therefore claim 37 is interpreted to encompass the method wherein the modifying does not include the alternative (iii), such as only (i) lowering the pH.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 17-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 12,624,348 (reference patent) in view of Horlitz et al. (WO 2013/045432 A1, 04 April 2013, provided by Applicant in IDS filed 14 Dec 2023) and Tosar et al. (Patel, T., ed., Extracellular RNA: Methods and Protocols, Methods in Molecular Biology, 2018, vol. 1740, p125-137, provided by Applicant in IDS filed 14 Dec 2023).
Reference claims 1-33 of the reference patent are drawn to a method for enriching extracellular DNA and sequentially extracellular vesicles and optionally extracellular RNA or for enriching extracellular vesicles and optionally extracellular RNA from a biological sample comprising extracellular DNA and extracellular vesicles, wherein the method comprises: (a) preparing a binding mixture comprising - the biological sample,- a solid phase comprising anion exchange groups, and- an acidic binding buffer comprising a buffering agent, and binding extracellular DNA to the solid phase comprising anion exchange groups; and (b) separating the solid phase with the bound extracellular DNA from the binding mixture to obtain a remaining binding mixture, wherein the remaining binding mixture comprises extracellular vesicles; and (c) processing the remaining binding mixture to enrich one or more biological targets of interest therefrom, wherein the processing comprises enriching extracellular vesicles and optionally extracellular RNA as biological targets of interest from the remaining binding mixture, wherein step (c) comprises enriching extracellular vesicles by binding to an anion exchange surface of a solid phase, wherein the binding conditions used in step (a) for binding extracellular DNA differ from the binding conditions used in step (c) for binding extracellular vesicles and optionally extracellular RNA, and wherein the different binding conditions in step (a) and step (c) are achieved by at least one selected from the group consisting of: (i) the extracellular vesicle binding mixture of step (c) has a lower pH than the extracellular DNA binding mixture of step (a); and (ii) a buffering agent introduced into the extracellular vesicle binding mixture in step (c) differs from the buffering agent in the extracellular DNA binding mixture in step (a). Reference claim 28 recites the method further comprises lysing enriched extracellular vesicles thereby providing a lysate that comprises vesicular RNA and optionally enriching RNA from the lysate. Reference claims 3-8 recite the pH of the acidic binding buffer, addressing limitations of claims 39-42. Reference claims 10-11 recite the acidic binding buffer comprising a carboxylic acid and a salt thereof, addressing limitations of claims 43-45. Reference claims 25-26 recite different conditions for step (a) and step (c), addressing limitations of claims 34-38.
Reference claims 1-33 do not specifically recite the extracellular RNA is non-vesicular RNA (claims 17 and 27).
Horlitz et al. teaches the state of the art regarding the isolation of extracellular nucleic acids as detailed above.
Tosar et al. teaches it is desired to isolate extracellular non-vesicular RNA to serve as a source for biomarker discovery complementary to extracellular vesicular RNA as detailed above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the Reference claims in view of Horlitz et al. and Tosar et al. in order to select the extracellular RNA to be extracellular non-vesicular RNA such as miRNA. One of ordinary skill in the art would have been motivated to combine the Reference claims in view of Horlitz et al. and Tosar et al. with a reasonable expectation of success because all of the Reference claims, Horlitz et al., and Tosar et al. are drawn to methods for isolation of extracellular nucleic acids including RNA, the Reference claims teach enriching extracellular RNA as a component different from extracellular vesicles and Reference claim 28 teaches the method enriching RNA from extracellular vesicles, and Tosar et al. teaches it is desired to isolate extracellular non-vesicular RNA such as miRNA to be complementary to extracellular vesicular RNA, suggesting it would have been obvious to select the extracellular RNA enriched according to the method of the Reference claims to be extracellular non-vesicular RNA.
Claims 17-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 35-37 and 43-71 of copending Application No. 17/785,251 (reference application) in view of Horlitz et al. (WO 2013/045432 A1, 04 April 2013, provided by Applicant in IDS filed 14 Dec 2023), Tosar et al. (Patel, T., ed., Extracellular RNA: Methods and Protocols, Methods in Molecular Biology, 2018, vol. 1740, p125-137, provided by Applicant in IDS filed 14 Dec 2023), and Filant et al. (Patel, T., ed., Extracellular RNA: Methods and Protocols, Methods in Molecular Biology, 2018, vol. 1740, p43-57, cited in PTO-892).
Reference claims 35-37 and 43-71 of the reference application are drawn to a method for enriching extracellular nucleic acids from a sample comprising extracellular vesicles, the method comprising the following steps: (aa) preparing an acidic binding mixture comprising the sample and an anion exchange solid phase and binding extracellular vesicles to the anion exchange solid phase; (bb) separating the anion exchange solid phase comprising the extracellular vesicles bound to the anion exchange solid phase from the binding mixture; (cc) non-chaotropically lysing the bound extracellular vesicles in the presence of at least one detergent to release vesicular nucleic acids and binding the released vesicular nucleic acids to the anion exchange solid phase; and (dd) separating the anion exchange solid phase with the bound nucleic acids from the lysate. Reference claim 36 recites the extracellular nucleic acids are extracellular RNA. Reference claim 37 recites further eluting the bound nucleic acids, addressing limitations of claim 22 and 32. Reference claim 48 recites limitations of the acidic binding mixture, addressing limitations of claims 39-45. Reference claims 66-71 recite a kit for performing the method according to claim 35, making obvious the method performed according to the recited intended use by using the kit as claimed.
Reference claims 35-37 and 43-71 of the reference application does not specifically recite method comprising enriching the extracellular non-vesicular RNA (claims 17 and 27).
Horlitz et al. teaches the state of the art regarding the isolation of extracellular nucleic acids as detailed above.
Tosar et al. teaches it is desired to isolate extracellular non-vesicular RNA to serve as a source for biomarker discovery complementary to extracellular vesicular RNA as detailed above.
Filant et al. teaches methods for isolating extracellular RNA as above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the Reference claims in view of Horlitz et al., Tosar et al., and Filant et al. in order to modify the method of the Reference claims by adding a further step of isolating the extracellular non-vesicular RNA. One of ordinary skill in the art would have been motivated to combine the Reference claims in view of Horlitz et al., Tosar et al., and Filant et al. with a reasonable expectation of success because all of the Reference claims, Horlitz et al., Tosar et al., and Filant et al. are drawn to methods of isolating extracellular nucleic acids such as RNA, and for similar reasoning detailed above regarding Horlitz et al., Tosar et al., and Filant et al., one of ordinary skill in the art would have been motivated to isolate both extracellular vesicular RNA and extracellular non-vesicular RNA because Tosar et al. and Filant et al. suggest it is desired to isolate both types of RNA and the combined teachings suggest different conditions are used for isolating extracellular vesicular RNA and extracellular non-vesicular RNA. See also MPEP 2144.05 at II. providing ““[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”In this case Horlitz et al. teaches the general conditions of the claim, and Tosar et al. and Filant et al. suggest it would have been obvious to one of ordinary skill in the art to perform routine experimentation to discover different optimal conditions for the different RNA isolation steps.
This is a provisional nonstatutory double patenting rejection.
The application under examination is deemed to have a later patent term filing date compared to the earlier-filed reference application. See MPEP 804 especially at I.B.1.(b).
Conclusion
No claim is found to be allowable.
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/JONATHAN S LAU/ Primary Examiner, Art Unit 1693
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