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 .
Applicant’s election without traverse of Group I claims 35-65 in the reply filed on 16 July 2025 is acknowledged. The election/restriction requirement is deemed proper and is therefore made FINAL. An Action on the merits of claims 35-65 is contained herein below. The Election/Restriction mailed 03 July 2025 mentions Group I, claims 1-65, which is incorrect. Group I should be claims 35-65 since claims 1-34 were canceled.
Group II Claims 66-71 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Priority
This application is a 371 of PCT/EP2020/086585 filed 12/16/2020. This application claims foreign priority to EPO EP19216752.6 filed 12/16/2019, under 35 U.S.C. 119(a)-(d). The certified copy of the foreign priority document has been filed in the instant application. The priority accorded is 12/16/2019.
Claim Rejections - 35 USC § 112
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 52 and 63 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 52 is drawn to the anion exchange particles having one or more characteristics and further in parts (iv) and (v) recites what type of reactions are used to attach the anion exchange groups. Does applicant intend the type of linkage resulting via the said reactions? If so, it should be reworded clearly. The said parts are not seen to recite the characteristics of the anion exchange particles.
Claim 63 recites ‘prior to step (a)’. There is no step (a) in claim 35. Does applicant intend step (aa)?
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.
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.
Claim(s) 35-65 are rejected under 35 U.S.C. 103 as being unpatentable over Stoll et al (WO 2017/197399 A1; cited in IDS filed 06/14/2022) in view of Horlitz et al (CN 103930546 A; Machine English Translation, pages 1-42) and further in view of Skog et al (WO 2016/007755 A1; cited in IDS filed 06/14/2022).
Stoll teaches a method for enriching extracellular nucleic acids from a sample comprising extracellular vesicles (Abstract; paras 003-005). The method comprises the steps of (a) providing a biological sample (b) contacting the biological sample with a capture surface to retain cell-free DNA and RNA and microvesicles from the sample on or in the capture surface (c) contacting the surface with an elution buffer to release the DNA/RNA to produce a homogenate and extracting the DNA or RNA from the homogenate. The solid capture surface is a bead. The solid surface is functionalized with a quaternary amines and tertiary amines. The capture surface can be positively charged and is an anion exchanger. The pH during microvesicle capture is ≤ 7 (paragraphs 7-9, 76, 134 and 134; part of the limitations of claim 35 regarding binding vesicles to anion exchange phase; limitation of claim 36 regarding nucleic acid being RNA; limitation of claim 37; limitation of claim 52-53, claim 57, part (iii) and (v); claim 58, part (v)). In view of this teaching one of ordinary skill in the art can select anion exchange solid phase particles for capturing and prepare the binding mixture in an acidic form as in claim 35, part (aa). According to Stoll the method further comprises a centrifugation step after contacting the biological sample with the capture surface (para 18). This is same as steps (bb), and (dd) in claim 35, which can be performed in the instant method. The elution buffer contains a detergent like Tween, Triton X-100, etc., which can disrupt the microvesicles and aid the elution of the nucleic acids from the capture surface. The elution buffer also allows for efficient lysis of the microvesicles for release and elution of the nucleic acids (para 68 and 79; step cc in claim 35; step ff in claim 37; limitation of claims 38, 43). The concentration of the detergent as in claim 39 can be determined by one of ordinary skill in the art. The biological sample can be a plasma, serum or urine sample (para 36, 119; page 41, claim 15 of Stoll; as in claim 62). According to Stoll the method can be used to isolate both DNA and RNA from biofluids (paras 107, 115-116). This means that cells from the body fluid can be removed and the cell-depleted body fluid can be provided as a sample as in claim 63, and the biological sample can be subjected to DNA depletion as in claim 64 if the target product is the nucleic acid. According to Stoll the solid surface can be magnetic (para 009; as in claim 51).
Stoll’s method further comprises a centrifugation step after contacting the biological sample with the capture surface (para 18). This is same as steps (bb), and (dd) in claim 35, which can be performed in the instant method. This step would give the anion exchange particles that are separated in step (dd) with bound extracellular RNA as in claim 46 since the method is for enriching both DNA and RNA. Stroll teaches the pH for binding and acidifying agents that can be used (paras 72-74). In view of this one of ordinary skill in the art can adjust the pH to be lower as in claims 49-50. According to Stoll its method is for isolation of extracellular vesicles and cell free nuclei acids (para 006). Therefore, in view of this and the teachings of the other references one of ordinary skill in the art can carry out the steps in claim 65 to obtain a sample comprising extracellular vesicles.
Even though Stoll teaches that the pH during microvesicle capture is ≤ 7 it does not expressly teach preparing an acidic binding mixture comprising the sample and the anion exchange solid phase as in step aa in claim 35, and does not teach the limitations of claims 40-42, 44-48, 54-56, 59-61.
Horlitz teaches a method of isolating extracellular nucleic acids from body fluids, which can be blood, plasma, serum or urine, comprising the steps (a) the extracellular nucleic acid is bound to a solid phase in the binding mixture at pH <6 which is acidic (b) separating solid phase with the bound nucleic acid (c) optionally washing the nucleic acid (c) eluting nucleic acid from solid phase and separating nucleic acid from eluent (paras 22-27, 69, 150-156; acidic binding mixture as in claim 35 aa). This combined teaching of Stoll and Horlitz provide the steps that can be used to enrich extracellular nucleic acid as in claim 35. Since Stoll teaches that vesicle lysis buffer comprises a detergent and the lysis buffer is of an ionic strength that is sufficient to allow for efficient adsorption of the nucleic acid on to the solid phase and Horlitz teaches that effective adsorption of nucleic acids to an anion solid phase is required to be carried under acidic conditions, it is obvious to use an acidic lysis reagent comprising a detergent to contact the anion exchange solid phase to which the vesicles are bound to lyse the vesicles as in claim 38.
Horlitz teaches that anion exchange groups can be monoamines, diamines, polyamines and nitrogen containing aromatic or aliphatic heterocyclic groups including X-(CH2)n-Y wherein X=Y=NH2 and n can be 0-20 (paras 125-131). In view of this the artisan would use the anion exchange groups as in claims 54-56 and 59-60 in the method, and would also use anion exchange groups having the number of ionizable groups per anion exchange groups as in claim 58. Horlitz also teaches the use of magnetic particles for the solid phase (para 122). According to Horlitz its method can be performed by using an automated system which can simultaneously process a plurality of samples and avoids operation error (para 67). In view of this teaching the artisan would find it obvious to use magnetic anion exchange particles and perform one or more steps using an automated system as in claim 61.
Skog, drawn to a method of enriching extracellular nucleic acids using charged anionic surfaces, teaches the use of anionic detergents like SDS and a buffering agent. The pH is set to 5.5 ≤ (paras 152-153; as in claims 40-42 and 47-48). Proteinase K can be added (para 221; as in claims 44-45).
MPEP 2141 states, "The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that "[R]ejections on obviousness cannot be sustained by mere conclusatory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.'" KSR, 550 U.S. at, 82 USPQ2d at 1396. Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) " Obvious to try " choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
According to the rationale discussed in KSR above, the rationale in (G) above is seen to be applicable here since based on the prior art teachings, the method steps including the anion exchange solid phase are known in the art for enriching extracellular nucleic acids from a sample comprising extracellular vehicles. Thus, it is obvious to combine prior art elements and arrive at the claimed method.
Thus, the claimed invention as a whole would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention over the combined teachings of the prior art. The artisan would be motivated to use the claimed method (also taught by the combined teachings of the prior art) since it is preferable to use method steps already known in the art to be used for enriching extracellular nucleic acids. According to the prior art, the method is simple and rapid for separating extracellular nucleic acid. It can be automated and allows for processing large volume samples also (Horlitz-para 0013). The method also provides for improved isolation of extracellular vesicles and co0isolation cell-free nuclei acids (Stoll-para 0006). These teachings provide additional motivation for the artisan to use the claimed method.
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
The USPTO Internet website contains Terminal Disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 35-38, 41-45, 47-62 and 64-65 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 35-39, 43-47, 52-70 of copending Application No. 17/785,478 (‘478) in view of Stoll et al (WO 2017/197399 A1; cited in IDS filed 06/14/2022) and further in view of Horlitz et al (CN 103930546 A; Machine English Translation, pages 1-42) and Skog et al (WO 2016/007755 A1; cited in IDS filed 06/14/2022). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 35 is drawn to a method of enriching extracellular nucleic acids from a sample comprising extracellular vesicles comprising preparing an acidic binding mixture comprising the sample and anion exchange solid phase, separating the solid phase comprising the bound extracellular vesicles, lysing the vesicles in the presence of at least one detergent to release nucleic acids, and separating anion exchange solid phase with the bound nucleic acids. Dependent claims 36-38, 41-45, 47-62 and 64-65 recite limitations drawn to nucleic acid being extracellular RNA, further steps of washing and eluting nucleic acids, use of detergent and buffering agent, pH of acidic lysis reagent, characteristics of lysis reagent, use of protease, proteinase K, characteristics of the acidic reagent, magnetic anion exchange particles, pH difference of binding mixture and ionized anion exchange group, characteristics of anion exchange particles and exchange groups, types of amino groups, number of ionizable groups, polymeric and polyallylamine groups, characteristics of the sample, , removal of cells from body fluid sample.
Copending claim 35 of ‘478 is drawn to a method of enriching extracellular DNA from a biological sample comprising the said DNA and extracellular vesicles by preparing a binding mixture comprising the biological sample, a solid phase comprising anion exchange groups and an acidic binding buffer and binding the extracellular DNA to the solid phase and separating the solid phase from the binding mixture wherein the remaining binding mixture comprises extracellular vesicles. The dependent claims recite limitations that overlap with those of the instant claims.
The copending claims of ‘478 differ from the instant claims in that the instant claims are drawn to method which includes extracellular nucleic acids which includes all types of nuclei acids whereas ‘478 is drawn to enriching extracellular DNA.
The teachings of the secondary references are set forth above.
It would have been obvious to one of ordinary skill in the art at the time of filing of the instant invention to arrive at the claimed method in view of the combined teachings o the cited prior art, since the secondary references teach that DNA, RNA and extracellular vesicles can be enriched using the claimed steps and also provide motivation for using the same.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
1. Elected claims 35-65 (Group I) are rejected.
2. Group II, claims 66-71 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GANAPATHY KRISHNAN whose telephone number is (571)272-0654. The examiner can normally be reached M-F 8.30am-5pm.
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/GANAPATHY KRISHNAN/Primary Examiner, Art Unit 1693