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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/28/2026 has been entered.
Claims Status
Claims 1, 2, 4, 6, 7, 17-23, & 25-29 filed on 01/28/2026 are pending. The cancellation of claim 5 without prejudice or disclaimer in the reply filed 01/28/2026 is acknowledged. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is Non-FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 102
Claim(s) 17-23, & 25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ritt (U.S. Patent Application Publication No. US 2011/0130558 A1), as cited on the IDS dated 05/16/2023.
Regarding amended claim 17, it is noted that the specification of the instant application teaches that it is believed that the larger cfDNA fragments enriched from a urine sample are predominantly post-glomerular cfDNA fragments (paragraph [0025] of instant specification). The instant specification further teaches that larger cfDNA fragments that are greater than 100 base pairs in length, such as between about 100 base pairs in length to 10,000 base pairs. Therefore, post-glomerular cfDNA fragments are given its broadest reasonable interpretation to encompass cfDNA fragments enriched from urine samples that are 100 base pairs in length or greater.
Ritt teaches a method for isolating and/or purifying (enriching) short-chain nucleic acids from freely circulating nucleic acids that do not contain cells (cfDNA) (paragraph [0029] lines 1-20) by binding nucleic acids to a nucleic acid-binding support material (DNA-binding particles) in the presence of a chaotropic compound and an alcohol in step (x) and in step (a) (form a reaction solution) (paragraph [0022] lines 1-4; paragraph [0023] lines 1-6; paragraph [0024] lines 1-9; paragraph [0025] lines 1-2; paragraph [0027] lines 1-14) in which the nucleic-acid binding support material is magnetic silica particles (DNA-binding particles) forming a particle fraction with bound nucleic acids and a non-particle fraction, and then eluting the bound nucleic acids (bound cfDNA) from the nucleic acid-binding material after step (x) or in step (b) according to the 2-step method (paragraph [0025] lines 1-2; paragraph [0027] lines 1-14). Ritt also teaches that the alcohol concentration in step (x) is ≤ 30% (v/v) (wherein the reaction solution has an alcohol concentration of at least 30% v/v) (paragraph [0026] lines 1-12). Ritt also teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≤
300 bp, and/or
≥
50 bp,
≥
100 bp in length (enriched with cfDNA fragments having different size distributions) (paragraph [0075] lines 1-14). In addition, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) from a biological sample comprising a urine sample and are, for example,
≥
100 bp in length (cfDNA fragments of post-glomerular cfDNA fragments) (paragraph [0075] lines 1-14).
Regarding claim 18, Ritt teaches the nucleic-acid binding support material is magnetic silica particles (DNA-binding particles) in which a magnetic field is applied to separate the bound nucleic acids (bound cfDNA) from the solution (paragraph [0072] lines 1-10; paragraph [0073] lines 1-6).
Regarding claim 19, Ritt teaches that the alcohol in the sample mixture (reaction solution) in step (a) of the 2-step method is at a concentration of
≥
25 to
≤
50% (v/v) (reaction solution has an alcohol concentration of greater than 45% v/v) (paragraph [0042] lines 1-3; paragraph [0045] line 1).
Regarding claim 20, Ritt teaches eluting the bound nucleic acids (bound cfDNA) from the nucleic acid-binding material (from the plurality of bead particles) after step (x) or in step (b) according to the 2-step method (paragraph [0025] lines 1-2; paragraph [0027] lines 1-14).
Regarding claim 21, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≥
100 bp and/or
≤
300 bp in length (enriched with cfDNA fragments of about 160 base pairs in length or of about 300 base pairs in length) (paragraph [0075] lines 1-14).
Regarding claim 22, Ritt teaches the alcohol in the sample during binding of the nucleic acids to the support material is isopropanol (isopropyl alcohol) (paragraph [0037] lines 1-7).
Regarding claim 23, Ritt teaches the biological sample is a urine sample (paragraph [0029] lines 1-3 & 9-13).
Regarding claim 25, Ritt teaches the method for isolating and/or purifying short-chain nucleic acids can also include a step (x) that precede steps (a) and (b) in a 2-step method wherein step (x) nucleic acids are bound to a nucleic acid-binding support material (DNA-binding particles) in the presence of a chaotropic compound and an alcohol and the alcohol is at a concentration of is ≤ 30% (v/v) (alcohol concentration is less than about 35% v/v) (paragraph [0022] lines 1-4; paragraph [0023] lines 1-6; paragraph [0024] lines 1-9; paragraph [0025] lines 1-2; paragraph [0026] lines 1-12; paragraph [0027] lines 1-14).
Response to Arguments
The response traverses the rejection. The response asserts that claim 17 has been amended to recite that “the reaction solution has an alcohol concentration of at least 30% v/v” and that regardless of whether claim 17 is interpreted as a single-step or open-ended enrichment process, Ritt expressly limits alcohol concentration for long nucleic acids (step(x), the first step) to below 30%, preferably ≤20% and therefore does not teach or suggest this limitation. These arguments have been thoroughly reviewed but were not found persuasive as Ritt teaches that the alcohol concentration in step (x) is ≤ 30% (v/v) (wherein the reaction solution has an alcohol concentration of at least 30% v/v) (paragraph [0026] lines 1-12). Therefore, Ritt teaches that the alcohol concentration is less than or equal to 30% v/v and appreciates a reaction solution that has an alcohol concentration of at least 30% as recited in claim 17 as currently amended. Further, it is not required that the limitations of a claim be taught in a preferred embodiment.
The response also asserts that Ritt does not teach the claimed method as a whole and thus cannot anticipate claim 17 and dependent claims 18-23, 25, 27, and 28. These arguments have been thoroughly reviewed but were not found persuasive for the reasons set forth above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 103
Claim(s) 1, 2, 4, 6, 7, 17-23, & 25-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ritt (U.S. Patent Application Publication No. US 2011/0130558 A1), as cited on the IDS dated 05/16/2023.
Regarding amended claim 1, Ritt teaches a method for isolating and/or purifying (enriching) short-chain nucleic acids from freely circulating nucleic acids that do not contain cells (cfDNA) (paragraph [0029] lines 1-20) by binding nucleic acids to a nucleic acid-binding support material (DNA-binding particles) in the presence of a chaotropic compound and an alcohol (form a reaction solution) (paragraph [0013] lines 1-5; paragraph [0014] lines 1-4) in which the nucleic-acid binding support material is magnetic silica particles (DNA-binding particles) forming a particle fraction with bound nucleic acids and a non-particle fraction, and then removing (eluting) the bound nucleic acids (bound cfDNA) from the nucleic acid-binding material according to the 1-step method (paragraph [0015] lines 1-2). Ritt also teaches that the alcohol in the sample mixture (reaction solution) is at a concentration of
≥
25% (v/v) (paragraph [0042] lines 1-3; paragraph [0044] line 1). In addition, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≥
100 bp in length (enriched with cfDNA fragments having a length of at least about 100 base pairs) (paragraph [0075] lines 1-14). Ritt also teaches the alcohol in the sample during binding of the nucleic acids to the support material is isopropanol (isopropyl alcohol) (paragraph [0037] lines 1-7). Finally, Ritt teaches that the size of the isolated (enriched) nucleic acids may be varied/ controlled by choosing the alcohol concentration in combination with the concentration of the chaotropic agent and adjusting the binding conditions (paragraph [0016] lines 1-21; paragraph [0017] lines 5-7; paragraph [0076] lines 1-10).
Ritt does not teach the concentration of isopropyl alcohol in the reaction solution is at least 55% v/v, however, optimizing reaction alcohol and chaotropic concentrations is prima facie obvious in view of the routine nature of reaction condition optimization taught in Ritt. As set for in the MPEP 2144.05 11 A:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.)…
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to modify the concentration of the isopropyl alcohol concentration in the reaction solution to vary/control the size of the isolated (enriched) nucleic acids as taught in Ritt due to the routine nature of reaction condition optimization.
Regarding claim 2, Ritt teaches the nucleic-acid binding support material is magnetic silica particles (DNA-binding particles) in which a magnetic field is applied to separate the bound nucleic acids (bound cfDNA) from the solution (paragraph [0072] lines 1-10; paragraph [0073] lines 1-6).
Regarding claim 4, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≥
100 bp and/or
≤
300 bp in length (enriched with cfDNA fragments of about 160 base pairs in length or of about 300 base pairs in length) (paragraph [0075] lines 1-14).
Regarding claim 6, Ritt teaches the biological sample is a urine sample (paragraph [0029] lines 1-3 & 9-13).
Regarding claim 7, it is noted that the specification of the instant application teaches that it is believed that the larger cfDNA fragments enriched from a urine sample are predominantly post-glomerular cfDNA fragments (paragraph [0025] of instant specification). The instant specification further teaches that larger cfDNA fragments that are greater than 100 base pairs in length, such as between about 100 base pairs in length to 10,000 base pairs. Therefore, post-glomerular cfDNA fragments are given its broadest reasonable interpretation to encompass cfDNA fragments enriched from urine samples that are 100 base pairs in length or greater.
Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) from a biological sample comprising a urine sample and are, for example,
≥
100 bp in length (cfDNA fragments consist essentially off post-glomerular cfDNA fragments) (paragraph [0075] lines 1-14).
Regarding amended claim 17, it is noted that the specification of the instant application teaches that it is believed that the larger cfDNA fragments enriched from a urine sample are predominantly post-glomerular cfDNA fragments (paragraph [0025] of instant specification). The instant specification further teaches that larger cfDNA fragments that are greater than 100 base pairs in length, such as between about 100 base pairs in length to 10,000 base pairs. Therefore, post-glomerular cfDNA fragments are given its broadest reasonable interpretation to encompass cfDNA fragments enriched from urine samples that are 100 base pairs in length or greater.
Ritt teaches a method for isolating and/or purifying (enriching) short-chain nucleic acids from freely circulating nucleic acids that do not contain cells (cfDNA) (paragraph [0029] lines 1-20) by binding nucleic acids to a nucleic acid-binding support material (DNA-binding particles) in the presence of a chaotropic compound and an alcohol in step (x) and in step (a) (form a reaction solution) (paragraph [0022] lines 1-4; paragraph [0023] lines 1-6; paragraph [0024] lines 1-9; paragraph [0025] lines 1-2; paragraph [0027] lines 1-14) in which the nucleic-acid binding support material is magnetic silica particles (DNA-binding particles) forming a particle fraction with bound nucleic acids and a non-particle fraction, and then eluting the bound nucleic acids (bound cfDNA) from the nucleic acid-binding material after step (x) or in step (b) according to the 2-step method (paragraph [0025] lines 1-2; paragraph [0027] lines 1-14). Ritt also teaches that the alcohol concentration in step (x) is ≤ 30% (v/v) (wherein the reaction solution has an alcohol concentration of at least 30% v/v) (paragraph [0026] lines 1-12). Ritt also teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≤
300 bp, and/or
≥
50 bp,
≥
100 bp in length (enriched with cfDNA fragments having different size distributions) (paragraph [0075] lines 1-14). In addition, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) from a biological sample comprising a urine sample and are, for example,
≥
100 bp in length (cfDNA fragments of post-glomerular cfDNA fragments) (paragraph [0075] lines 1-14).
Regarding claim 18, Ritt teaches the nucleic-acid binding support material is magnetic silica particles (DNA-binding particles) in which a magnetic field is applied to separate the bound nucleic acids (bound cfDNA) from the solution (paragraph [0072] lines 1-10; paragraph [0073] lines 1-6).
Regarding claim 19, Ritt teaches that the alcohol in the sample mixture (reaction solution) in step (a) of the 2-step method is at a concentration of
≥
25 to
≤
50% (v/v) (reaction solution has an alcohol concentration of greater than 45% v/v) (paragraph [0042] lines 1-3; paragraph [0045] line 1).
Regarding claim 20, Ritt teaches eluting the bound nucleic acids (bound cfDNA) from the nucleic acid-binding material (from the plurality of bead particles) after step (x) or in step (b) according to the 2-step method (paragraph [0025] lines 1-2; paragraph [0027] lines 1-14).
Regarding claim 21, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≥
100 bp and/or
≤
300 bp in length (enriched with cfDNA fragments of about 160 base pairs in length or of about 300 base pairs in length) (paragraph [0075] lines 1-14).
Regarding claim 22, Ritt teaches the alcohol in the sample during binding of the nucleic acids to the support material is isopropanol (isopropyl alcohol) (paragraph [0037] lines 1-7).
Regarding claim 23, Ritt teaches the biological sample is a urine sample (paragraph [0029] lines 1-3 & 9-13).
Regarding claim 25, Ritt teaches the method for isolating and/or purifying short-chain nucleic acids can also include a step (x) that precede steps (a) and (b) in a 2-step method wherein step (x) nucleic acids are bound to a nucleic acid-binding support material (DNA-binding particles) in the presence of a chaotropic compound and an alcohol and the alcohol is at a concentration of is ≤ 30% (v/v) (alcohol concentration is less than about 35% v/v) (paragraph [0022] lines 1-4; paragraph [0023] lines 1-6; paragraph [0024] lines 1-9; paragraph [0025] lines 1-2; paragraph [0026] lines 1-12; paragraph [0027] lines 1-14).
Regarding amended claim 26, Ritt teaches that in the 2-step method the breakthrough/supernatant from step (x) (non-particle fraction) is contacted with a nucleic-acid support material (DNA-binding particles) in the presence of a chaotropic compound and an alcohol in step (a) (form a second reaction solution) where the alcohol in the sample mixture (second reaction solution) in step (a) of the 2-step method is at a concentration of
≥
25% (v/v) (paragraph [0042] lines 1-3; paragraph [0044] line 1), and then eluting the bound nucleic acids from the nucleic acid-binding (DNA-binding) material in step (b) and the 2-step method (eluting the cfDNA fragments from the second plurality of DNA-binding particles (paragraph [0025] lines 1-2). Ritt also teaches the alcohol in the sample during binding of the nucleic acids to the support material is isopropanol (isopropyl alcohol) (paragraph [0037] lines 1-7). Finally, Ritt teaches that the size of the isolated (enriched) nucleic acids may be varied/ controlled by choosing the alcohol concentration in combination with the concentration of the chaotropic agent and adjusting the binding conditions (paragraph [0016] lines 1-21; paragraph [0017] lines 5-7; paragraph [0076] lines 1-10).
Ritt does not teach the concentration of isopropyl alcohol in the reaction solution is at least 55% v/v, however, optimizing reaction alcohol and chaotropic concentrations is prima facie obvious in view of the routine nature of reaction condition optimization taught in Ritt. As set for in the MPEP 2144.05 11 A:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.)…
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to modify the concentration of the isopropyl alcohol concentration in the reaction solution to vary/control the size of the isolated (enriched) nucleic acids as taught in Ritt due to the routine nature of reaction condition optimization.
Regarding amended claim 27, Ritt teaches the nucleic-acid binding support material is magnetic silica particles (DNA-binding particles) in which a magnetic field is applied to separate the bound nucleic acids (bound cfDNA) from the solution (paragraph [0072] lines 1-10; paragraph [0073] lines 1-6).
Regarding claim 28, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≥
50 bp in length (enriched with cfDNA fragments having a length of about 10 nucleotide base pairs to about 80 nucleotide base pairs) (paragraph [0075] lines 1-14).
Regarding claim 29, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≥
50 bp in length (paragraph [0075] lines 1-14). Ritt also teaches that the size of the isolated (enriched) nucleic acids may be varied/ controlled by choosing the alcohol concentration in combination with the concentration of the chaotropic agent and adjusting the binding conditions (paragraph [0016] lines 1-21; paragraph [0017] lines 5-7; paragraph [0076] lines 1-10).
Ritt does not teach that the eluate is enriched with cfDNA fragments having a length of about 30 nucleotides, however, optimizing reaction alcohol and chaotropic concentrations is prima facie obvious in view of the routine nature of reaction condition optimization taught in Ritt. As set for in the MPEP 2144.05 11 A:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.)…
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to obtain nucleic acids having a length of about 30 nucleotide base pairs through optimizing the alcohol concentration, the chaotropic agent concentration, and the binding conditions as taught in Ritt due to the routine nature of reaction condition optimization.
Claim(s) 1, 2, 4, 6, 7, & 26-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ritt (U.S. Patent Application Publication No. US 2011/0130558 A1), as cited on the IDS dated 05/16/2023, in view of Gemen (U.S. Patent No. Patent No. 6,465,639 B1), as cited in the IDS dated 05/16/2023.
The teachings of Ritt with respect to claim 17 & 25 are discussed above and incorporated herein.
Regarding amended claim 1, Ritt teaches a method for isolating and/or purifying (enriching) short-chain nucleic acids from freely circulating nucleic acids that do not contain cells (cfDNA) (paragraph [0029] lines 1-20) by binding nucleic acids to a nucleic acid-binding support material (DNA-binding particles) in the presence of a chaotropic compound and an alcohol (form a reaction solution) (paragraph [0013] lines 1-5; paragraph [0014] lines 1-4) in which the nucleic-acid binding support material is magnetic silica particles (DNA-binding particles) forming a particle fraction with bound nucleic acids and a non-particle fraction, and then removing (eluting) the bound nucleic acids (bound cfDNA) from the nucleic acid-binding material according to the 1-step method (paragraph [0015] lines 1-2). Ritt also teaches that the alcohol in the sample mixture (reaction solution) is at a concentration of
≥
25% (v/v) (paragraph [0042] lines 1-3; paragraph [0044] line 1). In addition, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≥
100 bp in length (enriched with cfDNA fragments having a length of at least about 100 base pairs) (paragraph [0075] lines 1-14). Ritt also teaches the alcohol in the sample during binding of the nucleic acids to the support material is isopropanol (isopropyl alcohol) (paragraph [0037] lines 1-7). Finally, Ritt teaches that the size of the isolated (enriched) nucleic acids may be varied/ controlled by choosing the alcohol concentration in combination with the concentration of the chaotropic agent and adjusting the binding conditions (paragraph [0016] lines 1-21; paragraph [0017] lines 5-7; paragraph [0076] lines 1-10).
Ritt does not teach the concentration of isopropyl alcohol in the reaction solution is at least 55% v/v.
Gemen teaches a method for isolating (enriching) nucleic acids by contacting the sample with a chaotropic substance, a nucleic acid binding solid phase, and an alcoholic solution (column 2 lines 32-45). Gemen teaches the method containing a series of method steps including a wash step that comprises using an alcohol concentration from about 60-70% (at least 55% v/v) and two subsequent washes with 70% ethanol alcohol or isopropanol (isopropyl) alcohol of about 50% (column 3 lines 25-38).
Ritt and Gemen are considered to be analogous to the claimed invention because they are all in the same field of isolating (enriching) nucleic acids. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of having a reaction solution with an isopropyl alcohol concentration of
≥
25% (v/v) in Ritt to incorporate a reaction solution with an higher isopropyl alcohol concentration, comprising of at least 55% v/v, as taught in Gemen by obvious to try from choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success.
Regarding claim 2, Ritt teaches the nucleic-acid binding support material is magnetic silica particles (DNA-binding particles) in which a magnetic field is applied to separate the bound nucleic acids (bound cfDNA) from the solution (paragraph [0072] lines 1-10; paragraph [0073] lines 1-6).
Regarding claim 4, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≥
100 bp and/or
≤
300 bp in length (enriched with cfDNA fragments of about 160 base pairs in length or of about 300 base pairs in length) (paragraph [0075] lines 1-14).
Regarding claim 6, Ritt teaches the biological sample is a urine sample (paragraph [0029] lines 1-3 & 9-13).
Regarding claim 7, it is noted that the specification of the instant application teaches that it is believed that the larger cfDNA fragments enriched from a urine sample are predominantly post-glomerular cfDNA fragments (paragraph [0025] of instant specification). The instant specification further teaches that larger cfDNA fragments that are greater than 100 base pairs in length, such as between about 100 base pairs in length to 10,000 base pairs. Therefore, post-glomerular cfDNA fragments are given its broadest reasonable interpretation to encompass cfDNA fragments enriched from urine samples that are 100 base pairs in length or greater.
Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) from a biological sample comprising a urine sample and are, for example,
≥
100 bp in length (cfDNA fragments consist essentially off post-glomerular cfDNA fragments) (paragraph [0075] lines 1-14).
Regarding amended claim 26, Ritt teaches that in the 2-step method the breakthrough/supernatant from step (x) (non-particle fraction) is contacted with a nucleic-acid support material (DNA-binding particles) in the presence of a chaotropic compound and an alcohol in step (a) (form a second reaction solution) where the alcohol in the sample mixture (second reaction solution) in step (a) of the 2-step method is at a concentration of
≥
25% (v/v) (paragraph [0042] lines 1-3; paragraph [0044] line 1), and then eluting the bound nucleic acids from the nucleic acid-binding (DNA-binding) material in step (b) and the 2-step method (eluting the cfDNA fragments from the second plurality of DNA-binding particles (paragraph [0025] lines 1-2). Ritt also teaches the alcohol in the sample during binding of the nucleic acids to the support material is isopropanol (isopropyl alcohol) (paragraph [0037] lines 1-7). Finally, Ritt teaches that the size of the isolated (enriched) nucleic acids may be varied/ controlled by choosing the alcohol concentration in combination with the concentration of the chaotropic agent and adjusting the binding conditions (paragraph [0016] lines 1-21; paragraph [0017] lines 5-7; paragraph [0076] lines 1-10).
Ritt does not teach the concentration of isopropyl alcohol in the second reaction solution is at least 55% v/v.
Gemen teaches a method for isolating (enriching) nucleic acids by contacting the sample with a chaotropic substance, a nucleic acid binding solid phase, and an alcoholic solution (column 2 lines 32-45). Gemen teaches the method containing a series of method steps including a wash step that comprises using an alcohol concentration from about 60-70% (at least 55% v/v) and two subsequent washes with 70% alcohol ethanol alcohol or isopropanol (isopropyl) alcohol of about 50% (column 3 lines 25-38).
Ritt and Gemen are considered to be analogous to the claimed invention because they are all in the same field of isolating (enriching) nucleic acids. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of having a reaction solution with an isopropyl alcohol concentration of
≥
25% (v/v) in Ritt to incorporate a reaction solution with an higher isopropyl alcohol concentration, comprising of at least 55% v/v, as taught in Gemen by obvious to try from choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success.
Regarding amended claim 27, Ritt teaches the nucleic-acid binding support material is magnetic silica particles (DNA-binding particles) in which a magnetic field is applied to separate the bound nucleic acids (bound cfDNA) from the solution (paragraph [0072] lines 1-10; paragraph [0073] lines 1-6).
Regarding claim 28, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≥
50 bp in length (enriched with cfDNA fragments having a length of about 10 nucleotide base pairs to about 80 nucleotide base pairs) (paragraph [0075] lines 1-14).
Regarding claim 29, Ritt teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≥
50 bp in length (paragraph [0075] lines 1-14). Ritt also teaches that the size of the isolated (enriched) nucleic acids may be varied/ controlled by choosing the alcohol concentration in combination with the concentration of the chaotropic agent and adjusting the binding conditions (paragraph [0016] lines 1-21; paragraph [0017] lines 5-7; paragraph [0076] lines 1-10).
Ritt does not teach that the eluate is enriched with cfDNA fragments having a length of about 30 nucleotides, however, optimizing reaction alcohol and chaotropic concentrations is prima facie obvious in view of the routine nature of reaction condition optimization taught in Ritt. As set for in the MPEP 2144.05 11 A:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.)…
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to obtain nucleic acids having a length of about 30 nucleotide base pairs through optimizing the alcohol concentration, the chaotropic agent concentration, and the binding conditions as taught in Ritt due to the routine nature of reaction condition optimization.
Response to Arguments
The response traverses the rejection. The response asserts that claim 1 and 26 have been amended to recite that the alcohol solution is isopropyl alcohol and that neither of the cited references, alone or in combination, teaches a binding step that involves combining isopropyl concentration of at least 55% and, moreover, a person of ordinary skill in the art would have neither a motivation to modify the cited reference to include such a step or a reasonable expectation of success in achieving the claimed result. This argument has been thoroughly reviewed but was not found persuasive. First, Ritt teaches a method for isolating and/or purifying (enriching) short-chain nucleic acids from freely circulating nucleic acids that do not contain cells (cfDNA) (paragraph [0029] lines 1-20) by binding nucleic acids to a nucleic acid-binding support material (DNA-binding particles) in the presence of a chaotropic compound and an alcohol (form a reaction solution) (paragraph [0013] lines 1-5; paragraph [0014] lines 1-4) in which Ritt teaches the alcohol in the sample during binding of the nucleic acids to the support material is isopropanol (isopropyl alcohol) (paragraph [0037] lines 1-7). Further, Gemen teaches a method for isolating (enriching) nucleic acids by contacting the sample with a chaotropic substance, a nucleic acid binding solid phase, and an alcoholic solution (column 2 lines 32-45). Gemen teaches the method containing a series of method steps including a wash step that comprises using an alcohol concentration from about 60-70% (at least 55% v/v) and two subsequent washes with 70% ethanol alcohol or isopropanol (isopropyl) alcohol of about 50% (column 3 lines 25-38). Specifically, Gemen teaches two alcohols, ethanol and isopropyl, both suitable for washing to enrich nucleic acids in a sample at two higher concentrations of between about 60-70% and about 50%. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of having a reaction solution with an isopropyl alcohol concentration of
≥
25% (v/v) in Ritt to incorporate a reaction solution with an higher isopropyl alcohol concentration, comprising of at least 55% v/v, as taught in Gemen by obvious to try from choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success.
The response also asserts that Gemen expressly distinguishes between ethanol and isopropanol stating ethanol used in the preferred concentration range of about 60-70% and isopropanol a preferred concentration of about 50%. Further, the response asserts that even when considered together, Ritt and Gemen provide no teaching or suggestion of using isopropanol at ≥55% v/v in a binding step and Gemen’s disclosure of 60-70% applies only to ethanol in the context of washing steps, not binding steps, and Gemen offers no indication that such concentration would be suitable or effective in the process described by Ritt as the functions and timing of alcohol use in the two references are materially different. Further, the response asserts that, accordingly, a person of ordinary skill in the art would lack motivation to combine these teachings to arrive at the claimed invention and there would be no reasonable expectation of success given Gemen’s explicit preference for lower isopropanol concentration and its silence regarding binding steps. These arguments have been thoroughly reviewed but were not found persuasive for the reasons set for above. In addition, Gemen does teach isolation (enrichment) of nucleic acids that is contacted with a chaotropic substance and a binding solid phase where the nucleic acid binding solid phase is subject to a washing procedure, comprising alcohol washing procedure, and therefore Gemen’s disclosure of high concentrations of alcohol is in the context of nucleic acid solid phase binding steps and the functions and timing of alcohol use is not materially different and Gemen is not silent regarding binding steps. Further, as discussed previously and above, Ritt and Gemen are focused on methods for isolating (enriching) nucleic acids with the use of reaction mixture comprising a chaotropic substance, a nucleic acid binding solid phase, and an alcoholic solution and Gemen teaches two alcohols, ethanol and isopropyl, both suitable for washing to enrich nucleic acids in a sample at two higher concentrations of between about 60-70% and about 50%. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of having a reaction solution with an isopropyl alcohol concentration of
≥
25% (v/v) in Ritt to incorporate a reaction solution with an higher isopropyl alcohol concentration, comprising of at least 55% v/v, as taught in Gemen by obvious to try from choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. In addition, Ritt teaches that the size of the isolated (enriched) nucleic acids may be varied/ controlled by choosing the alcohol concentration in combination with the concentration of the chaotropic agent and adjusting the binding conditions (paragraph [0016] lines 1-21; paragraph [0017] lines 5-7; paragraph [0076] lines 1-10), indicating optimization of alcohol concentration can vary/control the size of the isolated (enriched) nucleic acids providing a reasonable expectation of success that varying the alcohol concentration provides control when isolating (enriching) nucleic acids.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Double Patenting
Claim 1, 2, & 6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 & 3-5 of U.S. Patent No. 11,326,158 B2, in view of Ritt (U.S. Patent Application Publication No. US 2011/0130558 A1), as cited on the IDS dated 05/16/2023. Although the claims at issue are not identical, they are not patentably distinct from each other.
It is noted that is instant application claims it is a DIV of 16/510,365 in the Filing Receipt dated 07/06/2022. According to MPEP 201.06:
A later application for an independent or distinct invention, carved out of a nonprovisional application (including a nonprovisional application resulting from an international application or international design application), an international application designating the United States, or an international design application designating the United States and disclosing and claiming only subject matter disclosed in the earlier or parent application, is known as a divisional application. … A divisional application is often filed as a result of a restriction requirement made by the examiner.
A restriction was originally filed in the parent application, 16/510,365, which was then withdrawn in the office action dated 12/21/2020 of that parent application (16/510,365) as the claims were not patentably distinct from each other. Therefore, the instant application does not fit the definition of a division application and nonstatutory double patenting rejections have been applied.
Regarding amended claim 1 & claim 6, U.S. Patent No. 11,326,158 claims a method for enriching cfDNA fragments from a urine sample comprising contacting a urine sample from a first non-particle fraction with an alcoholic solution, a chaotropic agent, and a plurality of DNA-binding particles to form a reaction solution, wherein the reaction solution has an alcohol concentration of at least 55% v/v, separating the plurality of DNA-binding particles from the reaction solution thereby forming a particle fraction and a non-particle fraction, an eluting the cfDNA fragments from the plurality of DNA-binding particles from the particle fraction, wherein the eluate is enriched with cfDNA fragments have a length between 10 base pairs and 80 base pairs wherein a first particle fraction comprises post-glomerular cfDNA fragments and U.S. Patent No. 11,326,158 claims the alcohol of the reaction solution is isopropyl alcohol (see claims 1 & 5).
U.S. Patent No. 11,326,158 does not claim cfDNA fragments having a length of at least 100 base pairs.
Ritt teaches a method for isolating and/or purifying (enriching) short-chain nucleic acids from freely circulating nucleic acids that do not contain cells (cfDNA) (paragraph [0029] lines 1-20) by binding nucleic acids to a nucleic acid-binding support material (DNA-binding particles) in the presence of a chaotropic compound and an alcohol (form a reaction solution) (paragraph [0013] lines 1-5; paragraph [0014] lines 1-4). Ritt also teaches that short-chain nucleic acids of any particular length are concentrated (enriched) and are, for example,
≥
100 bp in length (enriched with cfDNA fragments having a length of at least about 100 base pairs) (paragraph [0075] lines 1-14). In addition, Ritt teaches that this method is capable of efficiently isolating and/or purifying (enriching) short-chain nucleic acids in which short-chain nucleic acids are important in various fields of applications such as prenatal diagnostics (paragraph [0010] lines 1-4; paragraph [0012] lines 1-5).
The claim would have been prima facie obvious to one of ordinary skill in the art to have modified the method of enriching cfDNA fragments having a length between 10 base pairs and 80 base pairs in claim 1 of U.S. Patent No. 11,326,158 to incorporate enriching short-chain nucleic acids that are
≥
100 bp in length as taught in Ritt because Ritt teaches that this method can efficiently enriching short-chain nucleic acids that are important for use and diagnostics in a variety of fields of application.
Regarding claim 2, U.S. Patent No. 11,326,158 claims the DNA-binding particles are silica magnetic particles wherein separating the plurality of silica magnetic particles comprises subjecting the reaction solution to a magnetic field (see claim 3).
Claim 17-20, 22, 23, & 25-29 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, & 18 of U.S. Patent No. 11,326,158 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
It is noted that is instant application claims it is a DIV of 16/510,365 in the Filing Receipt dated 07/06/2022. According to MPEP 201.06:
A later application for an independent or distinct invention, carved out of a nonprovisional application (including a nonprovisional application resulting from an international application or international design application), an international application designating the United States, or an international design application designating the United States and disclosing and claiming only subject matter disclosed in the earlier or parent application, is known as a divisional application. … A divisional application is often filed as a result of a restriction requirement made by the examiner.
A restriction was originally filed in the parent application, 16/510,365, which was then withdrawn in the office action dated 12/21/2020 of that parent application (16/510,365) as the claims were not patentably distinct from each other. Therefore, the instant application does not fit the definition of a division application and nonstatutory double patenting rejections have been applied.
Regarding claims 17, 19, 20, & 23, U.S. Patent No. 11,326,158 claims a method for enriching cfDNA fragments from a urine sample comprising contacting a urine sample from a first non-particle fraction with an alcoholic solution, a chaotropic agent, and a plurality of DNA-binding particles to form a reaction solution, wherein the first reaction solution has an alcohol concentration between 25-35% (at least 30% v/v) and the second reaction solution has an alcohol concentration of at least 55% v/v, separating the plurality of DNA-binding particles from the reaction solution thereby forming a particle fraction and a non-particle fraction, an eluting the cfDNA fragments from the plurality of DNA-binding particles from the particle fraction, wherein the eluate is enriched with cfDNA fragments have a length between 10 base pairs and 80 base pairs wherein a first particle fraction comprises post-glomerular cfDNA fragments (see claims 1 & 18).
Regarding claim 18, U.S. Patent No. 11,326,158 claims the DNA-binding particles are silica magnetic particles wherein separating the plurality of silica magnetic particles comprises subjecting the reaction solution to a magnetic field (see claim 3).
Regarding claim 22, U.S. Patent No. 11,326,158 claims the alcohol of the reaction solution is isopropyl alcohol (see claim 5).
Regarding claim 25, U.S. Patent No. 11,326,158 claims a method for enriching cfDNA fragments from a urine sample comprising contacting a urine sample with a first alcoholic solution, a first chaotropic agent, and a first plurality of DNA-binding particles to form a first reaction solution, wherein the first reaction solution has an alcohol concentration of 35% v/v or less, separating the first plurality of DNA-binding particles from the first reactions thereby forming a first particle fraction and a first non-particle fraction (see claim 1).
Regarding claim 26, U.S. Patent No. 11,326,158 claims a method for enriching cfDNA fragments from a urine sample by further contacting the first non-particle fraction with a second alcoholic solution and a second plurality of DNA-binding particles to form a second reaction solution wherein the second reaction solution has an alcohol concentration of at least 55% v/v, separating the second plurality of DNA-binding particles from the second reaction solution, thereby forming a second particle fraction and a second non-particle fraction, and eluting the cfDNA fragments from the second plurality of DNA-binding particles of the particle fraction and that the alcohol of the reaction solution is isopropyl alcohol (see claims 1 & 5).
Regarding claim 27, U.S. Patent No. 11,326,158 claims the DNA-binding particles are silica magnetic particles wherein separating the plurality of silica magnetic particles comprises subjecting the reaction solution to a magnetic field (see claim 3).
Regarding claim 28, U.S. Patent No. 11,326,158 claims the eluted cfDNA fragments having a length of between 10 base pairs and 80 base pairs (see claim 1).
Regarding claim 29, U.S. Patent No. 11,326,158 claims the eluate is enriched with cfDNA fragments of about 30 base pairs (see claim 4).
Response to Arguments
The response traverses the rejection. The response asserts that independent claim 1 has been amended to recite “the alcohol of the alcoholic solution is isopropyl alcohol” and claim 17 has been amended to recite that “the reaction solution has an alcoholic concentration of at least 30% v/v” and that all of the cited rejections rely on Ritt to bridge acknowledged gaps between the reference claims and the present claims. The response also asserts that, as noted above, Ritt fails to teach or suggest the limitations of the amended claims and therefore these rejections cannot be properly maintained in light of the amendments. This argument has been thoroughly reviewed but was not found persuasive as reference claim 5 of U.S. Patent No. 11,326,158 does claim the alcohol of the first reaction solution or the second reaction solution is isopropyl alcohol (the alcohol of the alcoholic solution is isopropyl alcohol) and reference claim 1 of U.S. Patent No. 11,326,158 does claim that the first reaction solution has an alcohol concentration of 35% v/v or less (the reaction solution has an alcoholic concentration of at least 30% v/v). Further, not all of the cited rejections under nonstatutory double patenting rely of Ritt to bridge the gaps between the reference claims and the present claims as only claims 1, 2, & 6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 & 3-5 of U.S. Patent No. 11,326,158 B2, in view of Ritt (U.S. Patent Application Publication No. US 2011/0130558 A1), as cited on the IDS dated 05/16/2023, as discussed previously and further above. Further, Ritt is used to bridge the gap of cfDNA fragments having a length of at least 100 base pairs between the reference claims and the present claims and therefore Ritt is not relied upon in the nonstatutory double patenting rejects for claims 1, 2, & 6 of the instant application for the amended limitations of “the alcohol of the alcoholic solution is isopropyl alcohol” as argued above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
Claims 1, 2, 4, 6, 7, 17-23, & 25-29 are rejected.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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