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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous office action has been withdrawn pursuant to 37 CFR 1.114.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 21 August 2025 has been entered.
The Request for Continued Examination filed has been considered. The following information has been made of record in the RCE filed for the instant application:
1. Claims 1-100 and 119 have been canceled.
2. New Claim 121 has been added.
3. Claims 101-106, 116 and 120 have been amended.
4. Response to rejections under 35 USC 112, 103 and double patenting.
The following rejection(s) is/are withdrawn:
5. The rejection of claims 102-105 under 35 USC 112 second paragraph has been overcome by amendments.
6. The rejection of Claims 102-106, 114-115 and 120 under 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends has been overcome by amendment.
Claims 101-118 and 120-121 are pending in the case.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 101 and 120 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 101 and 120 have been fully considered but are deemed to insert new matter into the claims since the specification as originally filed does not provide for the recitation, ‘below 10oC’.
At para 00150, the specification teaches the following:
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This means that step (b) can be performed at a temperature up to 0oC. The recitation ‘below10oC indicates that it can be any temperature below 0oC too. Consequently, there is nothing within the instant specification that would lead the artisan in the field to believe that Applicant was in possession of the invention as it is now claimed.
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.
Claim 101-118, and 120-121 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.
Amended claim 101 recites that the centrifuging is done ‘at below 10oC’. The recitation ‘at below’ is confusing. Is the centrifuging done at 10oC or below10oC? Moreover, below 10oC means it could be any temperature below 10oC. At para 00150, the specification teaches the following:
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Based on the teaching in the specification it is not clear at what temperature range the centrifuging step in claim 101, part (b) is performed. Step (c) in claim 101 recites eluting the microvesicles from the anion exchange membrane or the anion exchange bead after the centrifugation step. Is the elution also done at below 10oC or is it done after warming up to ambient temperature? The specification does not clarify the above, and there are no examples disclosed in the specification which clarify this.
Amended Claim 120 recites a temperature range of about 0oC to below 10oC in claim 101. At para 00150, the specification teaches the following:
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From the examples given 0oC is the lowest temperature at which the centrifugation is performed. However, the claim recites below 10oC, which is seen as including temperatures below 0oC. It is not clear what applicant intends regarding the temperature range in claim 120.
Claims 102-118, and 121, which depend from a rejected base claim that is unclear/indefinite are also rendered unclear/indefinite and are rejected for the same reasons. All claims which depend from an indefinite claim are also indefinite. Ex parte Cordova, 10 U.S.P.Q. 2d 1949, 1952 (P.T.O. Bd. App. 1989).
Response to Applicant’s Remarks
In view of the amendment the rejection under 35 USC 112 (b) is made of record.
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) 101-104, 106-113 and 120 are rejected under 35 U.S.C. 103 as being unpatentable over Lim et al (WO 2012/087241 A1; of record) in view of Rider et al (Scientific Reports, 2016, April, pages 1-14; of record) and further in view of Enderle et al (WO 2014/107571 A1; cited in IDS filed 12/21/2020; of record) and Skog et al (WO 2016/007755A1; cited in IDS filed 12/21/2020; of record).
Lim et al teaches a method of purifying/isolating microvesicles (exosomes) via applying them to an anion exchange capture surface wherein the surface is a membrane which has pores (page 2, lines 5-15; page 15, lines 25-28; page 16, lines 12-24; page 17, last paragraph and page 28, lines 5-10; part of the limitations of claim 101 regarding the method, anion exchange membrane as in claim 101, part (a)). The microvesicles can be eluted via a salt gradient (page 8, line 7; page 9, lines 3-7; page 9, line 15 through page 10, line 8; limitation of claim 101, part (b)). This also reads on the limitation of claim 102-using change in ionic strength. Changes in pH can also be used to effect separation (page 10 line 9; limitation of claim 103). The capture surface can be substituted with quaternary amino groups (page 14, lines 17-19; limitation of claim 108). The ion-exchange resin/membranes and particles (which reads on beads as in claim 101, part (a)) can be substituted with functional groups like sulfonate and tertiary amino groups (page 13, lines 15-23; as in claim 109). The method of Lim enables purification of exosomes from bodily fluids (page 28, lines 8-10). This tells one of ordinary skill in the art microvesicles/exosomes can be isolated/purified from bodily fluids like plasma, serum and urine as in claims 110, 112 and 113.
Lim et al does not teach the use of polyethylene glycol and its concentration as in claim 101, part (a), and the limitation of claims 104 and 120.
Rider et al teaches the use of PEG in a method of purifying exosomes (Abstract; PEG as in claim 101, part (a)). Even though Rider teaches the use of PEG in isolating vesicles from cell cultures and using centrifugation, one of ordinary skill in the art will have a reasonable expectation of success in using PEG as a crowding agent in the method of Lim et al since the method used to isolate viruses using PEG was adapted for isolation of vesicles using ultracentrifugation step (Abstract; page 1, last two lines through page 2, line 8). This tells one of ordinary skill in the art that the use of PEG can be adapted in the method of Lim et al. According to Rider an 8% PEG efficiently enriched vesicles (page 5, lines 8-9; percentage of PEG as in claim 101). The artisan will have a reasonable expectation of success that PEG will act as a crowding agent for the exosomes, and use of ion-exchange based method of a solution of exosomes and PEG, and will result in isolation of the microvesicles from a biological sample. In view of the teaching of Rider one of ordinary skill in the art can adjust the temperature during centrifugation to be at below ambient temperature as in claims 101 and 120 so that the exosomes do not precipitate, but stay adhered to the anion exchange material and can be eluted in step (c) as in claim 101.
Enderle, drawn to isolation of microvesicles, teaches isolation of nucleic acids like RNA from microvesicles via lysis (page 42, paras 203-204; as in claim 104). The capture surface can be beads which are magnetic (page 30, para 163; as in claim 107).
Skog et al drawn to isolating microvesicles and isolating nucleic acids, teaches lysis of the microvesicles and isolation of the nucleic acid from the vesicles via contact with silica column (Abstract and the Figure above abstract; page 28, para 176; page 41, claim 19 and page 42, claim 20; as in claims 104 and 106). The biological sample from which microvesicles and thence the nucleic acid is isolated can be plasma, serum or urine (as in claims 110 and 112). This also renders obvious the use of first catch urine as in claim 113. A suitable sample volume of the bodily fluid may be from 0.1ml to about 30ml (page 16, para 133; limitation of claim 111). The capture surface can be a membrane or beads (page 17, para 137; as in claim 101, part (a)).
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 use of a capture surface and PEG for isolation of microvesicles and extracting nucleic acids from microvesicles is individually taught in the art. Thus, it is obvious to combine prior art elements and arrive at the claimed method of isolating microvesicles and isolated nucleic acids from microvesicles.
Thus, the claimed invention as a whole would have been prima facie 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.
Method improvement is the motivation. The method allows for different microvesicles to be distinguished and purified. The method is also adaptable for small scale columns as well as high resolution and/or high capacity HPLC systems (Lim et al, page 6, last para).
Claim(s) 105, 114 and 115 are rejected under 35 U.S.C. 103 as being unpatentable over Lim et al (WO 2012/087241 A1; of record) in view of Rider et al (Scientific Reports, 2016, April, pages 1-14; of record) and further in view of Enderle et al (WO 2014/107571 A1; cited in IDS filed 12/21/2020; of record), Skog et al (WO 2016/007755A1; cited in IDS filed 12/21/2020; of record) and Basehore et al (WO 2006/138444 A1; of record).
The teachings of Lim, Rider, Enderle and Skog are set forth above. The cited art does not teach the limitations of claims 105, 114 and 115.
Basehore et al teaches that cells are commonly lysed with guanidine thiocyanate for isolating nucleic acids (para 006 and 017; limitation of claim 105 and part of the limitation of claim 114). b-mercaptoethanol is also included as a lysis buffer (para 005; limitation of claim 115). TCEP and a buffer are also included as reagents (para 053; as in claims 114 and 115). Cell lysis and isolation of nucleic acids involve exposing cells to detergents (para 004; as in claim 114). The artisan will find it obvious to use all of these agents in the instant method with a reasonable expectation of success.
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 use of a capture surface and PEG for isolation of microvesicles and extracting nucleic acids from microvesicles and the use of guanidine thiocyanate, detergent and buffer is individually taught in the art. Thus, it is obvious to combine prior art elements and arrive at the claimed method of isolating microvesicles and further lying the microvesicles and extract nucleic acids using the claimed reagents.
Thus, the claimed invention as a whole would have been prima facie 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.
Method improvement is the motivation. One of ordinary skill in the art will be motivated to use the claimed reagents since they are known in the art for the purpose for which they are used. The artisan would prefer to use the steps and reagents that are art tested and known to work well for isolation of nucleic acids.
Claim(s) 116-118 and new claim 121 are rejected under 35 U.S.C. 103 as being unpatentable over Lim et al (WO 2012/087241 A1; of record) in view of Rider et al (Scientific Reports, 2016, April, pages 1-14; of record) and further in view of Enderle et al (WO 2014/107571 A1; cited in IDS filed 12/21/2020; of record), Skog et al (WO 2016/007755A1; cited in IDS filed 12/21/2020; of record) and Xu et al (CN 104152436 A, Machine English Translation, pages 1-9; of record).
New claim 121 recites limitation drawn to isolating protein from the homogenate.
The teachings of Lim, Rider, Enderle and Skog are set forth above. The cited references do not teach the limitations of claims 116-118.
Xu et al, drawn to nucleic acid separation and purification, teaches the use of zinc ion for precipitating out proteins. Xu also teaches that the pH of the precipitation solution should be maintained at a stable value (para 0029; part of the limitations of claim 116 and limitations of claims 117-118). Therefore, the artisan can adjust the pH to be in the range recited in claim 116 for the purpose of optimization. It would be obvious to the artisan to isolate the protein from the homogenate as in claim 121 in view of Xu.
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 use of a capture surface and PEG for isolation of microvesicles and extracting nucleic acids from microvesicles and the use of guanidine thiocyanate, detergent, buffer, and the use of zinc for protein precipitation is individually taught in the art. Thus, it is obvious to combine prior art elements and arrive at the claimed method of isolating microvesicles and further lying the microvesicles and extract nucleic acids using the claimed reagents.
Thus, the claimed invention as a whole would have been prima facie 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.
Method improvement is the motivation. One of ordinary skill in the art will be motivated to use the claimed reagents since they are known in the art for the purpose for which they are used. The artisan would prefer to use the steps and reagents that are art tested and known to work well for isolation of nucleic acids.
Response to Applicant’s Remarks
Applicant has traversed the rejection of claims under 35 USC 103 arguing that the Examiner acknowledges that Lim fails to teach the limitation of claims 104 and 120. Applicant submits that one of ordinary skill in the art would readily acknowledge, based on the cited prior art, that if a biological sample that comprises PEG is cooled, including to below 10oC, it will precipitate the exosomes and be counter productive with the use of anion exchange chromatography or production of homogenate. Therefore, claim 101, as currently amended, further distinguishes the method disclosed in Lim or Rider. Enderle, Skog, nor Basehore remedy the deficiencies of Lim and Rider. For the above reasons the claims are not rendered obvious.
(Remarks-pages 6-8).
Applicant’s arguments have been considered but are not found to be persuasive. In Rider PEG was added to the culture media and refrigerated overnight for enriching exosomes. Cooling by refrigeration precipitated the exosomes. This is done to separate the exosomes from the culture medium. This does not mean that when the exosomes are in contact with the anion exchange membrane or bead and this is centrifuged at below 10oC the exosomes will precipitate. Applicant had earlier argued that Lim’s method is based on electrical charge, which means that contact of the exosomes with the anion exchange membrane or bead is due to charge. One of ordinary skill in the art will not expect the exosomes and the PEG solution in contact with the anion exchange bead or membrane to precipitate when centrifuged at below 10oC. If a biological sample that comprises PEG is cooled, including to below 10oC, it will precipitate the exosomes and be counterproductive with the use of anion exchange chromatography or production of homogenate, then what is it that is done differently in the claimed method that did not cause precipitation of the exosomes?
Lim teaches isolation of exosomes from bodily fluids using the anion exchange material via elution using a salt gradient. Rider’s teaching suggests that PEG can also be used in the isolation/purification of exosomes as in Lim. Rider also teaches the use of centrifugation. Therefore, the artisan will recognize that the teachings of Rider can be used in the method of Lim with a reasonable expectation of success. In view of the teachings of Rider one of ordinary skill in the art will determine a temperature range where the isolation of microvesicles is conducted in order to determine the temperature range in which centrifugation of the sample containing the microvesicles, PEG and the anion exchange material will not precipitate out so that it can further be used for elution of the microvesicles from the membrane or the bead in step (c) and lysis and production of homogenate as in step (d) as claimed. Such is well within the skill level of the artisan to recognize and perform. The rejection is maintained.
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 101-118 and 120-121 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 10,808,240 (‘240; of record) Rider et al (Scientific Reports, 2016, April, pages 1-14; of record and newly cited) and further in view of Enderle et al (WO 2014/107571 A1; cited in IDS filed 12/21/2020; of record and newly cited), Skog et al (WO 2016/007755A1; cited in IDS filed 12/21/2020; of record and newly cited), Basehore et al (WO 2006/138444 A1; of record and newly cited) and Xu et al (CN 104152436 A, Machine English Translation, pages 1-9; of record and newly cited). Although the conflicting claims are not identical, they are not patentably distinct from each other because:
Instant Claim 101 is drawn to a method isolating microvesicles from a biological sample by contacting the sample with a solid capture surface and PEG, wherein the capture surface is an anion exchange membrane or an anion exchange bead and eluting the microvesicles. Dependent claims 102-119 recite limitations drawn to change in ionic strength and pH for elution, further lysing the microvesicles and extracting nucleic acids, specific lysis reagents used, silica based solid surface, magnetic surface, functionalized membranes or beads, biological sample source, volume of the sample, guanidine thiocyanate, detergent and buffer, guanidine thiocyanate and an additional agent, adding protein precipitation buffer having a specific pH range, the precipitation buffer being a transition metal ion and future zinc ion and the percentage of PEG used. Claim 120 recites limitation drawn to ambient temperature range and new claim 121 is drawn to isolating protein from the homogenate.
Claim 1 of ‘240 is drawn to a method of extracting DNA and RNA from biological sample using contact with a capture surface and PEG and guanidinium thiocyanate and extracting the nucleic acids by further contacting with silica-based surface. Dependent claims 2-14 recite limitations that are seen in instant dependent claims 102-109.
The teachings of the secondary references are set forth above.
Claims 1-14 of ‘240 differ from the instant claims in that the instant claims are drawn to isolating microvesicles and then further extracting nucleic acids from the isolated microvesicles, whereas ‘240 is drawn to isolating nucleic acids via lysing microvesicles on the capture surface and centrifuging the biological sample containing the anion exchange membrane or the anion exchange bead and the chemical crowding agent at below 10oC and lysing the microvesicles eluted from the anion exchange membrane or bead in step (c) thereby producing a homogenate. However, it would have been obvious to one of ordinary skill in the art at the time the invention was made that the process of ‘240 could be modified to arrive at the claimed method in view of the secondary references.
In the instant case ‘240 teaches performing each of the steps applicant claims using the claimed reagents. Although the claims of '240 perform the lysis on the capture surface itself, one of ordinary skill in the art would readily recognize that the scheme taught by '240 could be modified in view of the secondary references to arrive at the instant invention with a reasonable expectation of success. The use of known steps and reagents in methods of isolation taught in the prior art is not seen to render the instantly claimed method unobvious over the art. Once the general scheme has been shown to be old, the burden is on the applicant to present reason or authority for believing that the same scheme with modification cannot be used in the instant method of isolating microvesicles first and then extracting nucleic acids from it.
Claims 101-118 and 120-121 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over as being unpatentable over claims 1-5 and 13 of U.S. Patent No. 10, 465, 183 (‘183; of record), and as being unpatentable over claims 1-5 and 10-14 of U.S. Patent No. 11,268,085 (‘085; of record) in view of Lim et al (WO 2012/087241 A1; of record) and further in view of Rider et al (Scientific Reports, 2016, April, pages 1-14; of record), Enderle et al (WO 2014/107571 A1; cited in IDS filed 12/21/2020; of record), Skog et al (WO 2016/007755A1; cited in IDS filed 12/21/2020; of record) and Xu et al (CN 104152436 A, Machine English Translation, pages 1-9; of record and newly cited).
Although the conflicting claims are not identical, they are not patentably distinct from each other because:
Instant Claim 101 is drawn to a method isolating microvesicles from a biological sample by contacting the sample with a solid capture surface and PEG, wherein the capture surface is an anion exchange membrane or an anion exchange bead and eluting the microvesicles. Dependent claims 102-119 recite limitations drawn to change in ionic strength and pH for elution, further lysing the microvesicles and extracting nucleic acids, specific lysis reagents used, silica based solid surface, magnetic surface, functionalized membranes or beads, biological sample source, volume of the sample, guanidine thiocyanate, detergent and buffer, guanidine thiocyanate and an additional agent, adding protein precipitation buffer having a specific pH range, the precipitation buffer being a transition metal ion and future zinc ion and the percentage of PEG used. Claim 120 recites limitation drawn to ambient temperature range and new claim 121 is drawn to isolating protein from the homogenate.
Claim 1 of ‘183 is drawn to extracting DNA and microvesicular RNA via contact of a biological sample with a capture surface, wherein the surface is beads functionalized with quaternary ammonium, contacting the surface with lysis reagent to produce a homogenate and extracting the RNA and DNA. Dependent claims 2-5 and 13 recite limitations drawn to quaternary ammonium functionalization of beads, biological sample being plasma or serum or urine, volume of biological sample and guanidinium as lysis reagent.
Claims 1 and 11 of ‘085 is drawn to a method of extracting DNA and microvesicular RNA via contact of a biological sample with a capture surface, wherein the surface is a membrane functionalized with quaternary ammonium, contacting the surface with guanidinium based buffer and extracting the RNA and DNA. Dependent claims 2-5, 10 and 12-14 are drawn to quaternary ammonium functionalization, biological sample being urine, volume of biological sample.
Claims 1-5 and 13 of ‘183 and claims 1-5 and 10-14 of ‘085 differ from the instant claims in that the instant claims are drawn to isolating microvesicles and then further extracting nucleic acids from the isolated microvesicles and also use PEG as an agent, whereas the claims of ‘183 and ‘085 are drawn to isolation of DNA and RNA and do not use PEG as a reagent. However, it would have been obvious to one of ordinary skill in the art at the time the invention was made that the process of ‘183 and ‘085 could be modified to arrive at the claimed method of first isolating the microvesicles and then lysing them to extract nucleic acids in view of the teachings of the secondary references, the teachings of which are set forth above.
In the instant case ‘183 and ‘085 teach performing each of the steps applicant claims using some of the claimed reagents and capture surface. Although the claims of '183 and ‘085 do not use PEG, one of ordinary skill in the art would readily recognize that the scheme taught by '183 and ‘085 in view of the secondary references could be modified to arrive at the instant invention with a reasonable expectation of success. The use of known methods and reagents in methods of isolation/purification taught in the prior art is not seen to render the instantly claimed method unobvious over the art. Once the general scheme has been shown to be old, the burden is on the applicant to present reason or authority for believing that the same scheme with modification in view of the secondary references cannot be used in the instant method of isolating microvesicles.
It is well established that merely selecting proportions and ranges and modifying the process conditions such as temperature, reaction time and concentration is not a patentable modification absent a showing of criticality (In re Aller, 220 F.2d, 454, 105 U.S.P.Q 233 C.C.P.A, 1995 and In re Becket, 33 U.S.P.Q 33, C.C.P.A, 1937 and In re Russell, 439 F. 2d 1228, 169 U.S.P.Q. 426, C.C.P.A 1971).
Response to Applicant’s Remarks
Applicant has traversed the double patenting rejections of record arguing that the claims of the ‘183 patent nor the claims of the ‘085 patent recite ‘…(b) centrifuging the biological sample containing the at least one anion exchange membrane or the at least one anion exchange bead and the chemical crowding agent at below 10oC… and “…(d) lysing the microvesicles eluted form the anion exchange membrane and bead in (c), thereby producing a homogenate” Therefore, applicant asserts that the currently pending claims of the present application are patentably distinct from the claims of ‘183 and the ‘085 patent and request that the double patenting rejections be withdrawn (Remarks page 8).
Applicant’s arguments are not persuasive. The amendment does not add any patentable distinction to the instant claims over those of the cited patents. The patents teach the same method steps and other limitations as claimed. The reasons given by the Examiner for maintaining the rejections under 35 USC 103 also apply here. The double patenting rejections are maintained.
Conclusion
1. Pending claims 101-118 and 120-121 are rejected.
2. Claims 1-100 and 119 have been canceled.
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/GANAPATHY KRISHNAN/Primary Examiner, Art Unit 1693