The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to Applicant’s amendments/remarks received November 12, 2025.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 19-24, 26-30 are canceled. Claims 1-18, 25, 31-35, 36-52 are under consideration.
Priority: This application is a 371 of PCT/EP2020/050006, filed January 2, 2020, which claims benefit to foreign application EP 19150438, filed January 4, 2019. A copy of the foreign priority document has been received in the instant application on June 21, 2021, and is in the English language.
Objections and Rejections
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.
Claims 18, 25, 36-43, 44-45 are rejected under 35 U.S.C. 103 as being unpatentable over Wyrich et al. (WO 2014146780; IDS 11.11.21, previously cited) and Mohan (2003 CalBioChem® Buffers Guide: 37 pages; previously cited). Wyrich et al. disclose methods, compositions, devices for stabilizing extracellular nucleic acid population in a cell-containing biological sample (at least abstract). Wyrich et al. disclose a stabilizing composition comprising butanamide, a caspase inhibitor, EDTA, a solvent and/or buffering agent, and one or more poly(oxyethylene) polymers, where the stabilizing composition is suitable for stabilizing cell-containing biological samples, including urine (at least p. 52 lines 39 to p. 53 lines 21; instant claim 18). Wyrich et al. disclose a collection device comprising the stabilizing composition (at least p. 58-60; instant claim 25). Wyrich et al. disclose the stabilizing composition is comprised in a solvent, e.g. water, a buffer, e.g. biological buffer such as MOPS, TRIS, PBS, and the like, and used for stabilization of cell-containing biological samples (at least p. 34 lines 4-7). While Wyrich et al. disclose that the butanamide is used in a concentration that exerts a stabilizing effect on the nucleic acid population (p. 14 lines 6-8), Wyrich et al. also disclose that a lower butanamide concentration of < 2% (w/v) is particularly effective when additionally using a further stabilizing agent such as a caspase inhibitor and/or a compound according to formula 1 (p. 14 lines 31-34). Wyrich et al. disclose that a compound of formula 1 is effective in achieving a stabilizing effect either alone or when being used in addition to butanamide (p. 19 lines 5-7).
Mohan discloses biological buffers for biological applications have distinctive characteristics including exhibiting pKa values at or near physiological pH (at least p. 10). Mohan discloses commonly used buffers include among others phosphate buffered saline (PBS) having a pH 7.4 (p. 22), tris buffered saline (TBS) having a pH 7.4, (p. 23), tris pKa 8.3 (p. 13), MOPS pKa 7.2 (p. 13).
It would have been obvious to one of ordinary skill in the art before the effect filing date of the claimed invention to arrive at the claimed stabilizing composition comprising a caspase inhibitor, EDTA, a solvent and a buffering agent, and one or more poly(oxyethylene) polymers, where the composition does not comprise a butanamide (instant claims 18, 25, 36-43), and a collection device comprising the claimed stabilizing composition (instant claims 18, 25, 36-43), and where the stabilizing composition is buffered and has a pH of ~7.4 because Wyrich et al. disclose biological buffers including MOPS, TRIS, PBS, for the stabilizing composition which does not need to include butanamide, where such biological buffers are known to have a pH ~7.0-7.4 (Mohan), and biological samples, which are known to have a physiological pH ~7.4.
Regarding instant claim 36, Wyrich et al. disclose the at least one poly(oxyethylene) polymer is polyethylene glycol (at least p. 51 lines 22-24).
Regarding instant claim 38, Wyrich et al. disclose the stabilizing composition comprises butanamide, a caspase inhibitor, EDTA, a solvent and/or buffering agent, and one or more poly(oxyethylene) polymers, where the poly(oxyethylene) polymer is polyethylene glycol, where the stabilization achieves stabilization of extracellular nucleic acid (at least p. 66 lines 1-20). As also noted above, Wyrich et al. also disclose that a lower butanamide concentration of < 2% (w/v) is particularly effective when additionally using a further stabilizing agent such as a caspase inhibitor and/or a compound according to formula 1 (p. 14 lines 31-34), where a formula 1 compound is a primary, secondary, tertiary amide (p. 19 lines 24-26). Wyrich et al. disclose that a compound of formula 1 is effective in achieving a stabilizing effect either alone or when being used in addition to butanamide (p. 19 lines 5-7). Wyrich et al. disclose the chelating agents can include combinations with other chelating agents, such as EDTA and salts of carboxylic acids such as citrate (at least p. 30 lines 15-34). Therefore, it would have been obvious to arrive at the recited stabilizing composition comprising EDTA, sodium citrate, at least one polyethylene glycol, a caspase inhibitor, a buffering agent, an amide, where the composition does not comprise butanamide, where the components disclosed in the stabilizing composition of Wyrich et al. would include a preservative having antimicrobial effects (i.e. EDTA, sodium citrate). The motivation to do so is given by Wyrich et al., which disclose the same components recited are included in a composition for stabilizing cell-containing samples, including urine samples. One of ordinary skill would have a reasonable expectation of success because Wyrich et al. disclose the same components recited form a composition for stabilizing cell-containing samples, including urine samples.
Regarding instant claim 39, Wyrich et al. disclose the stabilizing composition is a liquid (at least p. 51 line 20). Wyrich et al. disclose an EDTA concentration in the range selected from 0.05 mM to 100 mM (at least p. 57 lines 33-35, p. 65 lines 26-27). Wyrich et al. disclose the stabilizing composition is contacted with the urine sample at a volumetric ratio selected from 1:1 to 1:10, including 1:2 to 1:5 (at least p. 67 lines 17-22). Therefore, it would have been obvious to arrive at the recited liquid stabilizing composition comprising EDTA at 100mM up to the solubility limit, sodium citrate, at least one polyethylene glycol, a caspase inhibitor, a buffering agent, an amide, a pH ~7.4, and a ratio of stabilizing composition to sample of 1:1 to 1:10, including 1:2 to 1:5, where the components disclosed in the stabilizing composition of Wyrich et al. would include a preservative having antimicrobial effects (i.e. EDTA, sodium citrate). The motivation to do so is given by Wyrich et al., which disclose the same components recited are included in a composition for stabilizing cell-containing samples, including urine samples. One of ordinary skill would have a reasonable expectation of success because Wyrich et al. disclose the same components recited form a composition for stabilizing cell-containing samples, including urine samples.
Regarding instant claim 41, it is noted that the claim is still drawn to the recited stabilizing composition regardless of the result to be achieved recited in the wherein clause.
Regarding instant claim 42, Wyrich et al. disclose the container is an evacuated tube (at least p. 59 lines 31-40 ).
Regarding instant claim 43, Wyrich et al. disclose the container comprises the stabilizing composition in liquid form to collect the cell-containing sample where the volumetric ratio of the stabilizing composition to the cell-containing sample is selected from 1:1 to 1:10 and 1:2 to 1:5 (at least p. 60 lines 30-40).
Regarding instant claims 44-45, as noted above, Wyrich et al. disclose a collection device comprising the stabilizing composition (at least p. 58-60) and the collection is for collecting urine (at least p. 60 lines 18-19), where the stabilizing composition is comprised in a solvent, e.g. water, a buffer, e.g. biological buffer such as MOPS, TRIS, PBS, and the like, and used for stabilization of cell-containing biological samples (at least p. 34 lines 4-7). Therefore, it would have been obvious to arrive at the recited device comprising a urine sample and the stabilizing composition at a pH ~7.4 for the stabilizing composition and stabilized sample because Wyrich et al. disclose biological buffers including MOPS, TRIS, PBS, for the stabilizing composition, where such biological buffers are known to have a pH ~7.0-7.4 (Mohan), and biological samples, which are known to have a physiological pH ~7.4.
Reply: Applicant’s amendments/remarks have been considered but they are not persuasive.
Applicant has amended instant claim 18 to recite that the stabilizing composition does not comprise butanamide.
Applicant asserts that Wyrich et al. in combination with Mohan do not teach or suggest a stabilizing composition that does not comprise butanamide as recited in the amended claims. Applicant asserts that specifically, Wyrich et al. relate to using butanamide in stabilizing the extracellular nucleic acid population in a cell-containing sample (see Wyrich et al. abstract, p. 6 last paragraph).
Applicant’s remarks are not persuasive. It is known that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). MPEP 2123. Further, MPEP 2144.04 also notes that omission of an element is obvious.
In this instance, while Wyrich et al. disclose that the butanamide is used in a concentration that exerts a stabilizing effect on the nucleic acid population (p. 14 lines 6-8), Wyrich et al. also disclose that a lower butanamide concentration of < 2% (w/v) is particularly effective when additionally using a further stabilizing agent such as a caspase inhibitor and/or a compound according to formula 1 (p. 14 lines 31-34), where a formula 1 compound is a primary, secondary, tertiary amide (p. 19 lines 24-26). Wyrich et al. disclose that a compound of formula 1 is effective in achieving a stabilizing effect either alone or when being used in addition to butanamide (p. 19 lines 5-7).
Therefore, Wyrich et al. fairly disclose not including an amount of butanamide in the stabilizing composition when additional stabilizing agents such as caspase inhibitor and/or an amide compound are incorporated into the stabilizing composition.
Applicant asserts that the present application discloses unexpected surprising properties in the stabilizing compositions that do not contain butanamide and that it was surprising that the stabilizing composition not containing butanamide have similar stabilization properties of urine samples to stabilizing compositions containing butanamide. Applicant asserts that the results are surprising because Wyrich et al. disclose butanamide as a requisite component of stabilizing reagents.
Applicant’s remarks are not persuasive. Wyrich et al. has also disclosed that a lower butanamide concentration of < 2% (w/v) is particularly effective when additionally using a further stabilizing agent such as a caspase inhibitor and/or a compound according to formula 1 (p. 14 lines 31-34). Wyrich et al. also disclose that a compound of formula 1 is effective in achieving a stabilizing effect when used alone without butanamide (p. 19 lines 5-7). Therefore, Wyrich et al. fairly disclose not including an amount of butanamide in the stabilizing composition when additional stabilizing agents such as caspase inhibitor and/or an amide compound are incorporated into the stabilizing composition and further where the stabilizing composition achieves similar stabilization levels as compositions containing butanamide. Therefore, Applicant’s remarks that it was surprising that not including butanamide in compositions achieved stabilization are not persuasive because the prior art Wyrich et al. has already disclosed that not including an amount of butanamide in the stabilizing composition when additional stabilizing agents such as caspase inhibitor and/or an amide compound are present is also particularly effective.
In this instance, Wyrich et al. disclose the same components in a stabilizing composition for the same purpose of stabilizing an extracellular nucleic acid population in a cell-containing biological urine sample and at about the same pH recited. Wyrich et al. also disclose that an amount of butanamide < 2% (w/v), which includes 0%, is particularly effective (see teachings of Wyrich et al. above).
Therefore, Applicant’s remarks regarding unexpectedly superior and/or surprising properties are not persuasive.
Claims 1-18, 25, 31-52 are rejected under 35 U.S.C. 103 as being unpatentable over Wyrich et al. (WO 2014146780; IDS 11.11.21, previously cited) in view of Mohan (2003 CalBioChem® Buffers Guide: 37 pages; previously cited), and evidenced by Qiagen (QIAamp® DNA Micro Handbook for purification of genomic DNA 2014: 40 pages; previously cited). The teachings of Wyrich et al. and Mohan are noted above.
As noted above, Wyrich et al. disclose methods, compositions, devices for stabilizing extracellular nucleic acid population in a cell-containing biological sample (at least abstract). Wyrich et al. disclose a method for stabilization, comprising contacting the cell-containing sample with the stabilizing composition comprising butanamide, a caspase inhibitor, EDTA, a solvent and/or buffering agent, and one or more poly(oxyethylene) polymers, where the poly(oxyethylene) polymer is polyethylene glycol, where the stabilization achieves stabilization of extracellular nucleic acid (at least p. 66 lines 1-20), where the cell-containing sample is selected from among others urine samples (at least p. 66 lines 30-34, 41), where the stabilization does not involve a cross-linking agent (at least p. 66 lines 26-27). Wyrich et al. disclose the stabilizing composition is comprised in a solvent, e.g. water, a buffer, e.g. biological buffer such as MOPS, TRIS, PBS, and the like, and used for stabilization of cell-containing biological samples (at least p. 34 lines 4-7). As also noted above, Wyrich et al. disclose that a lower butanamide concentration of < 2% (w/v) is particularly effective when additionally using a further stabilizing agent such as a caspase inhibitor and/or a compound according to formula 1 (p. 14 lines 31-34), where a formula 1 compound is a primary, secondary, tertiary amide (p. 19 lines 24-26), and where that a compound of formula 1 is effective in achieving a stabilizing effect when used alone without butanamide (p. 19 lines 5-7). Therefore, Wyrich et al. disclose not including an amount of butanamide in the stabilizing composition when additional stabilizing agents such as caspase inhibitor and/or an amide compound are incorporated into the stabilizing composition.
Mohan discloses biological buffers for biological applications have distinctive characteristics including exhibiting pKa values at or near physiological pH (at least p. 10). Mohan discloses commonly used buffers include among others phosphate buffered saline (PBS) having a pH 7.4 (p. 22), tris buffered saline (TBS) having a pH 7.4, (p. 23), tris pKa 8.3 (p. 13), MOPS pKa 7.2 (p. 13).
Qiagen discloses DNA should be maintained at pH > 7.0 and is subject to degradation by acid hydrolysis (at least p. 12).
It would have been obvious one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed method for stabilizing a urine sample comprising contacting the urine with a stabilizing composition comprising a caspase inhibitor, EDTA, a solvent and a buffering agent, at least one poly(oxyethylene) polymer where the at least one poly(oxyethylene) polymer is polyethylene glycol, where the components disclosed in the stabilizing composition of Wyrich et al. include a preservative having antimicrobial effects (i.e. EDTA), and further where the stabilizing composition is buffered, has a pH of ~7.4, and does not involve a cross-linking agent and does not comprise a butanamide (instant claims 1-5, 7, 9, 11, 12, 15, 18, 36-37, 40-41, 47, 50). The motivation to do so is given by Wyrich et al., which disclose the same components recited are included in a composition for stabilizing cell-containing samples, including urine samples. It would have been obvious to arrive at a pH ~7.4 for the stabilizing composition and stabilized sample because Wyrich et al. disclose biological buffers including MOPS, TRIS, PBS, for the stabilizing composition, where such biological buffers are known to have a pH ~7.0-7.4 (Mohan), and biological samples, which are known to have a physiological pH ~7.4, and it is further known that DNA should be stabilized and/or maintained at a pH > 7.0 (Qiagen p. 12). One of ordinary skill would have a reasonable expectation of success because Wyrich et al. disclose the same components recited form a composition for stabilizing cell-containing samples, including urine samples.
Regarding instant claim 4, Wyrich et al. disclose the chelating agents can include combinations with other chelating agents, such as EDTA and salts of carboxylic acids such as citrate (at least p. 30 lines 15-34). Therefore, it would be obvious to combine another chelating agent (i.e. agent for inhibiting bacterial growth) such as sodium citrate with the EDTA in the stabilized composition of Wyrich et al.
Regarding instant claims 5, 7, as noted above, Wyrich et al. disclose the stabilizing composition is comprised in a solvent, e.g. water, a buffer, e.g. biological buffer such as MOPS, TRIS, PBS, and the like, and used for stabilization of cell-containing biological samples (at least p. 34 lines 4-7). Therefore, it would be obvious to arrive at a pH ~7.4 for the stabilizing composition and stabilized sample because Wyrich et al. disclose biological buffers including MOPS, TRIS, PBS, for the stabilizing composition, where such biological buffers are known to have a pH ~7.0-7.4 (Mohan), and biological samples, which are known to have a physiological pH ~7.4, and it is further known that DNA should be stabilized and/or maintained at a pH > 7.0 (Qiagen p. 12).
Regarding instant claim 6, Wyrich et al. disclose the stabilizing composition is contacted with the urine sample at a volumetric ratio selected from 1:1 to 1:10, including 1:2 to 1:5 (at least p. 67 lines 17-22).
Regarding instant claim 8, Wyrich et al. disclose an EDTA concentration in the range selected from 0.05 mM to 100 mM (at least p. 57 lines 33-35, p. 65 lines 26-27). Wyrich et al. disclose an EDTA concentration in the sample is in the range 0.5 to 40 mg/mL, including 20 mg/mL (at least p. 57 lines 37-41). It is known that “where 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). MPEP 2144.05. It would have been obvious to arrive at the recited EDTA concentration of 100 mM up to the solubility limit in the stabilized composition of Wyrich et al. and where the EDTA concentration in the sample is in the range 20 mg/mL-40 mg/mL in the method of stabilizing a urine sample as disclosed in Wyrich et al. by routine optimization.
Regarding instant claim 10, Wyrich et al. disclose the sample is contacted with at least one poly(oxyethylene) polymer, which is a high molecular weight poly(oxyethylene) polymer having a molecular weight of at least 1500 and a low molecular weight poly(oxyethylene) polymer (at least p. 63 lines 15-24), where it would be obvious to one of ordinary skill that the low molecular weight poly(oxyethylene) polymer is less than the molecular weight of 1500 (which has been identified as the high molecular weight poly(oxyethylene) polymer in Wyrich et al.).
Regarding instant claims 13, 38, 48, as noted above, Wyrich et al. disclose the stabilizing composition comprises butanamide, a caspase inhibitor, EDTA, a solvent and/or buffering agent, and one or more poly(oxyethylene) polymers, where the poly(oxyethylene) polymer is polyethylene glycol, where the stabilization achieves stabilization of extracellular nucleic acid (at least p. 66 lines 1-20). Wyrich et al. disclose the sample is contacted with at least one poly(oxyethylene) polymer, which is a high molecular weight poly(oxyethylene) polymer having a molecular weight of at least 1500, including 3000, or 4500-10000, and a low molecular weight poly(oxyethylene) polymer (at least p. 63 lines 15-24). As also noted above, Wyrich et al. also disclose that a lower butanamide concentration of < 2% (w/v) is particularly effective when additionally using a further stabilizing agent such as a caspase inhibitor and/or a compound according to formula 1 (p. 14 lines 31-34), where a formula 1 compound is a primary, secondary, tertiary amide (p. 19 lines 24-26). Wyrich et al. disclose that a compound of formula 1 is effective in achieving a stabilizing effect either alone or when being used in addition to butanamide (p. 19 lines 5-7). Wyrich et al. disclose the chelating agents can include combinations with other chelating agents, such as EDTA and salts of carboxylic acids such as citrate (at least p. 30 lines 15-34). Therefore, it would have been obvious to arrive at the recited stabilizing composition comprising EDTA, sodium citrate, a high molecular weight polyethylene glycol having a molecular weight of at least 3000, a low molecular weight polyethylene glycol having a molecular weight of less than 1000, a caspase inhibitor, a buffering agent, an amide, where the composition does not comprise butanamide, where the components disclosed in the stabilizing composition of Wyrich et al. would include a preservative having antimicrobial effects (i.e. EDTA, sodium citrate). The motivation to do so is given by Wyrich et al., which disclose the same components recited are included in a composition for stabilizing cell-containing samples, including urine samples. One of ordinary skill would have a reasonable expectation of success because Wyrich et al. disclose the same components recited form a composition for stabilizing cell-containing samples, including urine samples.
Regarding instant claims 14, 39, 49, as noted above, Wyrich et al. disclose the same components recited in the instant claims and at the same amounts, concentrations, and/or conditions (see above). Wyrich et al. disclose the stabilizing composition is a liquid (at least p. 51 line 20). Therefore, it would have been obvious to arrive at the recited liquid stabilizing composition comprising EDTA at 100mM up to the solubility limit, sodium citrate, a high molecular weight polyethylene glycol having a molecular weight of at least 6000, a low molecular weight polyethylene glycol having a molecular weight of less than 1000, a caspase inhibitor, a buffering agent, an amide, a pH ~7.4, and a ratio of stabilizing composition to sample of 1:1 to 1:10, including 1:2 to 1:5, where the components disclosed in the stabilizing composition of Wyrich et al. would include a preservative having antimicrobial effects (i.e. EDTA, sodium citrate). The motivation to do so is given by Wyrich et al., which disclose the same components recited are included in a composition for stabilizing cell-containing samples, including urine samples. One of ordinary skill would have a reasonable expectation of success because Wyrich et al. disclose the same components recited form a composition for stabilizing cell-containing samples, including urine samples.
Regarding instant claim 15, Wyrich et al. disclose the stabilizing composition stabilizes extracellular DNA in the cell-containing sample, the cell-containing sample being urine (at least p. 36 lines 9-15, 19, 23).
Regarding instant claim 25, Wyrich et al. disclose a collection device comprising the stabilizing composition (at least p. 58-60), where as noted above, the stabilizing composition comprises a caspase inhibitor, EDTA, a solvent and/or buffering agent, at least one poly(oxyethylene) polymer where the at least one poly(oxyethylene) polymer is polyethylene glycol, where the components disclosed in the stabilizing composition of Wyrich et al. include a preservative having antimicrobial effects (i.e. EDTA), and further where the stabilizing composition is buffered, has a pH of ~7.4, and does not involve a cross-linking agent and does not comprise a butanamide.
Regarding instant claims 31-32, Wyrich et al. disclose a urine collection device for collecting the sample (at least p. 60 lines 17-19) and a container comprising the stabilizing composition, in dried form (at least p. 58-60). Therefore, it would have been obvious to arrive at the recited step of collecting urine in a container (instant claim 31) and then transferring a sample of the collected urine to the container comprising the stabilizing composition that is in dried form to thereby contact the urine sample with the stabilizing composition (instant claim 32), where as noted above, the stabilizing composition comprises a caspase inhibitor, EDTA, a solvent and/or buffering agent, at least one poly(oxyethylene) polymer where the at least one poly(oxyethylene) polymer is polyethylene glycol, where the components disclosed in the stabilizing composition of Wyrich et al. include a preservative having antimicrobial effects (i.e. EDTA), and further where the stabilizing composition has a pH of ~7.4 and does not involve a cross-linking agent and does not comprise a butanamide.
Regarding instant claims 33-34, Wyrich et al. disclose that the urine collection device can also comprise the stabilizing composition comprising EDTA, in dried form (at least p. 59 lines 17 to p. 60 lines 40).
Regarding instant clams 16-17, 35, Wyrich et al. disclose further processing the stabilized sample to provide a cell sample and a cell-depleted portion and further isolating nucleic acids, including isolating extracellular nucleic acids from the cell-depleted portion of the stabilized sample and isolating nucleic acids from the cells removed from the stabilized sample (at least p. 67 lines 24 to p. 69 lines 4).
Regarding instant claim 42, Wyrich et al. disclose the container is an evacuated tube (at least p. 59 lines 31-40 ).
Regarding instant claim 43, Wyrich et al. disclose the container comprises the stabilizing composition in liquid form to collect the cell-containing sample where the volumetric ratio of the stabilizing composition to the cell-containing sample is selected from 1:1 to 1:10 and 1:2 to 1:5 (at least p. 60 lines 30-40).
Regarding instant claims 44-45, as noted above, Wyrich et al. disclose a collection device comprising the stabilizing composition (at least p. 58-60) and the collection is for collecting urine (at least p. 60 lines 18-19), where the stabilizing composition is comprised in a solvent, e.g. water, a buffer, e.g. biological buffer such as MOPS, TRIS, PBS, and the like, and used for stabilization of cell-containing biological samples (at least p. 34 lines 4-7). Therefore, it would have been obvious to arrive at the recited device comprising a urine sample and the stabilizing composition at a pH ~7.4 for the stabilizing composition and stabilized sample because Wyrich et al. disclose biological buffers including MOPS, TRIS, PBS, for the stabilizing composition, where such biological buffers are known to have a pH ~7.0-7.4 (Mohan), and biological samples, which are known to have a physiological pH ~7.4, and it is further known that DNA should be stabilized and/or maintained at a pH > 7.0 (Qiagen p. 12).
Regarding instant claim 46, Wyrich et al. disclose an EDTA concentration of 100 mM to 500 mM (at least p. 52 lines 6-8).
Regarding instant claims 51-52, Wyrich et al. disclose after a stabilization period, the method comprises further processing the stabilized sample to provide a cell sample and a cell-depleted portion and further isolating nucleic acids, including isolating extracellular nucleic acids from the cell-depleted portion of the stabilized sample and isolating nucleic acids from the cells removed from the stabilized sample (at least p. 67 lines 24 to p. 69 lines 4).
Reply: Applicant’s amendments/remarks have been considered but they are not persuasive. The reasons for maintaining Wyrich et al. are the same as noted above.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-18, 25, 31-35, 36-52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-5, 7-8, 10, 13-17, 20-23, 34, 37-60 of copending Application No. 15125863 (‘863) (reference application) in view of Wyrich et al. (supra), Mohan (supra), and Qiagen (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘863 application claims are drawn to a method for stabilizing a cell-containing biological sample comprising contacting the cell-containing biological sample with a chelating agent and one or more poly(oxyethylene) polymers, including a high molecular weight poly(oxyethylene) polymer and a low molecular weight poly(oxyethylene) polymer, an amide, a caspase inhibitor, and compositions comprising a chelating agent and one or more poly(oxyethylene) polymers. The ‘863 application claims differ from the instant claims by not explicitly reciting that the cell-containing biological sample is a urine sample and that the stabilizing composition is at a pH ~7.4. However, in view of the teachings of Wyrich et al., Mohan, and Qiagen noted above, it would have been obvious to one of ordinary skill to incorporate the urine sample of Wyrich et al. for the cell-containing biological sample in the ‘863 applications claims, and to further arrive at a stabilizing pH of ~7.4 that is buffered because Qiagen discloses DNA should be maintained at pH > 7.0 and is subject to degradation by acid hydrolysis (at least p. 12), thereby arriving at the instant claims. The motivation to do so given by Wyrich et al., which disclose that the components recited in the instant claims and the ‘863 application claims, including a chelating agent and one or more poly(oxyethylene) polymers, including a high molecular weight poly(oxyethylene) polymer and a low molecular weight poly(oxyethylene) polymer, an amide, a caspase inhibitor, are recognized components in a composition for stabilizing cell-containing biological samples, including urine samples, and Qiagen, which discloses that DNA should be maintained at pH > 7.0. One of ordinary skill would have a reasonable expectation of success because Wyrich et al. disclose the same components recited form a composition for stabilizing cell-containing samples, including urine samples.
Further regarding the instant dependent claims, if a component and/or element is not explicitly recited in the ‘863 application claims, it would have been obvious to incorporate the noted component and/or element into the ‘863 application claims in view of the teachings of Wyrich et al. noted above and at the recited pH ranges in view of the teachings of Qiagen above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reply: Applicant’s amendments/remarks have been considered but they are not persuasive. The provisional nonstatutory double patenting rejection is maintained for the reasons noted above.
Claims 1-18, 25, 31-35, 36-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-22, 24-27, 29-32, 34-40 of U.S. Patent No. 11203777 (‘777) in view of Wyrich et al. (supra), Mohan (supra), and Qiagen (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘777 patent claims are drawn to a method for stabilizing a cell-containing biological sample comprising contacting the cell-containing biological sample with a chelating agent and one or more poly(oxyethylene) polymers, including a high molecular weight poly(oxyethylene) polymer and a low molecular weight poly(oxyethylene) polymer, an amide, a caspase inhibitor, and compositions comprising a chelating agent and one or more poly(oxyethylene) polymers. The ‘777 patent claims differ from the instant claims by not explicitly reciting that the cell-containing biological sample is a urine sample and that the stabilizing composition is at a pH ~7.4. However, in view of the teachings of Wyrich et al., Mohan, and Qiagen, noted above, it would have been obvious to one of ordinary skill to incorporate the urine sample of Wyrich et al. for the cell-containing biological sample in the ‘777 patent claims, and to further arrive at a stabilizing pH of ~7.4 that is buffered because Qiagen discloses DNA should be maintained at pH > 7.0 and is subject to degradation by acid hydrolysis (at least p. 12), thereby arriving at the instant claims. The motivation to do so given by Wyrich et al., which disclose that the components recited in the instant claims and the ‘777 patent claims, including a chelating agent and one or more poly(oxyethylene) polymers, including a high molecular weight poly(oxyethylene) polymer and a low molecular weight poly(oxyethylene) polymer, an amide, a caspase inhibitor, are recognized components in a composition for stabilizing cell-containing biological samples, including urine samples, and Qiagen, which discloses that DNA should be maintained at pH > 7.0. One of ordinary skill would have a reasonable expectation of success because Wyrich et al. disclose the same components recited form a composition for stabilizing cell-containing samples, including urine samples.
Further regarding the instant dependent claims, if a component and/or element is not explicitly recited in the ‘777 patent claims, it would have been obvious to incorporate the noted component and/or element into the ‘777 patent claims in view of the teachings of Wyrich et al. noted above and at the recited pH ranges in view of the teachings of Qiagen above.
Reply: Applicant’s amendments/remarks have been considered but they are not persuasive.
Applicant asserts that claim 1 of the ‘777 patent recites that the composition provided in a) irradiated for sterilization in b) does not comprise a biological sample to be stabilized from a human or animal subject. Applicant asserts that thus, one of ordinary skill would not have been motivated to modify the claimed methods of the ‘777 patent in view of the cited references for stabilizing urine samples.
Applicant’s remarks are not persuasive. It is disclosed in the ‘777 patent specification that “It should be understood that in the method according to the first aspect of the invention, the composition provided in step a) and irradiated in step b) has not yet been contacted with a biological sample to be stabilized. It is the stabilization composition as such, i.e. the reagent without the biological sample, that is irradiated for sterilization. Accordingly, the composition provided in step a) and irradiated in step b) has not yet been contacted with a biological sample and hence, does not comprise a biological sample in steps a) and b)” (col. 15 lines 40-49).
Therefore, the ‘777 patent claims are reciting that the composition when being provided as a sterilized composition does not comprise a human/animal biological sample and not that the sterilized composition cannot be combined with a human/animal biological sample in a method for stabilizing extracellular nucleic acid. The ‘777 patent claim 18 expressly recites a method for stabilizing an extracellular nucleic acid population comprised in a cell-containing biological sample, where step b) recites contacting the cell-containing biological sample with the sterilized composition for stabilization.
Therefore, Applicant’s remarks regarding the nonstatutory double patenting rejection over the ‘777 patent claims are not persuasive.
Claims 1-18, 25, 31-35, 36-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6-7, 9-20 of U.S. Patent No. 11525155 (‘155) in view of Wyrich et al. (supra), Mohan (supra), and Qiagen (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘155 patent claims are drawn to method for stabilizing a cell-containing biological sample comprising contacting the cell-containing biological sample with a poly(oxyethylene) polymer, an amide, a caspase inhibitor, and claims reciting compositions comprising one or more poly(oxyethylene) polymers, wherein the cell-containing biological sample is a urine sample (at least claims 1, 9, 17 of the ‘155 patent). The ‘155 patent claims differ from the instant claims by not explicitly reciting a chelating agent and that the stabilizing composition is at a pH ~7.4. However, in view of the teachings of Wyrich et al., Mohan, and Qiagen, noted above, it would have been obvious to one of ordinary skill to incorporate a chelating agent of Wyrich et al. with the poly(oxyethylene) polymer, amide, caspase inhibitor of the ‘155 patent claims, and to further arrive at a stabilizing pH of ~7.4 that is buffered because Qiagen discloses DNA should be maintained at pH > 7.0 and is subject to degradation by acid hydrolysis (at least p. 12), thereby arriving at the instant claims. The motivation to do so is given by Wyrich et al., which disclose that the components recited in the instant claims and the ‘155 patent claims, including a chelating agent and one or more poly(oxyethylene) polymers, including a high molecular weight poly(oxyethylene) polymer and a low molecular weight poly(oxyethylene) polymer, an amide, a caspase inhibitor, are recognized components in a composition for stabilizing cell-containing biological samples, including urine samples, and Qiagen, which discloses that DNA should be maintained at pH > 7.0. One of ordinary skill would have a reasonable expectation of success because Wyrich et al. disclose the same components recited form a composition for stabilizing cell-containing samples, including urine samples.
Further regarding the instant dependent claims, if a component and/or element is not explicitly recited in the ‘155 patent claims, it would have been obvious to incorporate the noted component and/or element into the ‘155 patent claims in view of the teachings of Wyrich et al. noted above and at the recited pH ranges in view of the teachings of Qiagen above.
Reply: Applicant’s amendments/remarks have been considered but they are not persuasive.
Applicant asserts that the claims of the ‘155 patent require the use of a carboxylic acid amide in stabilizing biological samples and that claim 3 of the ‘155 patent specifically recites butanamide.
Applicant’s remarks are not persuasive. Claim 3 of the ‘155 patent has been removed from the nonstatutory double patenting. However, the nonstatutory double patenting over the ‘155 patent claims are maintained for the reasons noted above. The ‘155 patent specification discloses that the carboxylic acid amide can be selected from formamide, acetamide, propenamide, which is not butanamide.
Claims 1-18, 25, 31-35, 36-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-11, 14-16, 18-20 of U.S. Patent No. 10724074 (‘074) in view of Wyrich et al. (supra), Mohan (supra), and Qiagen (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘074 patent claims are drawn to a method for stabilizing a cell-containing biological sample comprising contacting the cell-containing biological sample with an amide, caspase inhibitor, and claims reciting compositions comprising an amide and caspase inhibitor. The ‘074 patent claims differ from the instant claims by not explicitly reciting that the cell-containing biological sample is a urine sample, a chelating agent, and poly(oxyethylene) polymers comprising a high molecular weight poly(oxyethylene) polymer and a low molecular weight poly(oxyethylene) polymer and that the stabilizing composition is at a pH ~7.4. However, in view of the noted teachings of Wyrich et al., Mohan, and Qiagen, noted above, it would have been obvious to one of ordinary skill to incorporate the urine sample of Wyrich et al. for the cell-containing biological sample in the ‘074 patent claims and to further incorporate a chelating agent and poly(oxyethylene) polymers comprising a high molecular weight poly(oxyethylene) polymer and a low molecular weight poly(oxyethylene) polymer with the amide and caspase inhibitor of the ‘074 patent claims, and to further arrive at a stabilizing pH of ~7.4 that is buffered because Qiagen discloses DNA should be maintained at pH > 7.0 and is subject to degradation by acid hydrolysis (at least p. 12), thereby arriving at the instant claims. The motivation to do so is given by Wyrich et al., which disclose that the components recited in the instant claims and the ‘074 patent claims, including a chelating agent and one or more poly(oxyethylene) polymers, including a high molecular weight poly(oxyethylene) polymer and a low molecular weight poly(oxyethylene) polymer, an amide, a caspase inhibitor, are recognized components in a composition for stabilizing cell-containing biological samples, including urine samples, and Qiagen, which discloses that DNA should be maintained at pH > 7.0. One of ordinary skill would have a reasonable expectation of success because Wyrich et al. disclose the same components recited form a composition for stabilizing cell-containing samples, including urine samples.
Further regarding the instant dependent claims, if a component and/or element is not explicitly recited in the ‘074 patent claims, it would have been obvious to incorporate the noted component and/or element into the ‘074 patent claims in view of the teachings of Wyrich et al. noted above and at the recited pH ranges in view of the teachings of Qiagen above.
Reply: Applicant’s amendments/remarks have been considered but they are not persuasive.
Applicant asserts that the claims of the ‘074 patent require use of the N,N-dialkylpropanamide (which is similar to butanamide, is also a carboxylic acid amide) in stabilizing biological samples.
Applicant’s remarks are not persuasive. The instant claims recite that the composition does not comprise a butanamide. The instant claims do not recite that the composition does not comprise a carboxylic acid. In this instance, the ‘074 patent claims do not recite a butanamide; therefore, the compositions recited in the ‘074 patent claims can be deemed to not comprise butanamide.
Claims 1-18, 25, 31-35, 36-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-20, 22-27 of U.S. Patent No. 10676780 (‘780) in view of Wyrich et al. (supra), Mohan (supra), and Qiagen (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both instant claims and the ‘780 patent claims are drawn to a method for stabilizing a cell-containing biological sample comprising contacting the cell-containing biological sample with an amide, caspase inhibitor, and claims reciting compositions comprising an amide and caspase inhibitor. The ‘780 patent claims differ from the instant claims by not explicitly reciting that the cell-containing biological sample is a urine sample, a chelating agent, and poly(oxyethylene) polymers comprising a high molecular weight poly(oxyethylene) polymer and a low molecular weight poly(oxyethylene) polymer and that the stabilizing composition is at a pH ~7.4. However, in view of the noted teachings of Wyrich et al., Mohan, and Qiagen, noted above, it would have been obvious to one of ordinary skill to incorporate the urine sample of Wyrich et al. for the cell-containing biological sample in the ‘780 patent claims and to further incorporate a chelating agent and poly(oxyethylene) polymers comprising a high molecular weight poly(oxyethylene) polymer and a low molecular weight poly(oxyethylene) polymer with the amide and caspase inhibitor of the ‘780 patent claims, and to further arrive at a stabilizing pH of ~7.4 that is buffered because Qiagen discloses DNA should be maintained at pH > 7.0 and is subject to degradation by acid hydrolysis (at least p. 12), thereby arriving at the instant claims. The motivation to do so is given by Wyrich et al., which disclose that the components recited in the instant claims and the ‘780 patent claims, including a chelating agent and one or more poly(oxyethylene) polymers, including a high molecular weight poly(oxyethylene) polymer and a low molecular weight poly(oxyethylene) polymer, an amide, a caspase inhibitor, are recognized components in a composition for stabilizing cell-containing biological samples, including urine samples, and Qiagen, which discloses that DNA should be maintained at pH > 7.0. One of ordinary skill would have a reasonable expectation of success because Wyrich et al. disclose the same components recited form a composition for stabilizing cell-containing samples, including urine samples.
Further regarding the instant dependent claims, if a component and/or element is not explicitly recited in the ‘780 patent claims, it would have been obvious to incorporate the noted component and/or element into the ‘780 patent claims in view of the teachings of Wyrich et al. noted above and at the rec