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 .
Priority
Acknowledgment is made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d). A certified copy of Parent Application 2021-090433, filed in Japan on 28 May 2021 has been received.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis 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 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3-6, 8 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Esteron; Aaron (US 20140360944 A1) in view of Walenciak, Matthew et al. (US 20040043505 A1).
Regarding claim 1, Esteron discloses a blood collection container (¶ [0001], [0008], a system for obtaining a cellular fraction … comprising: (a) a collection tube for collecting a cell suspension (1));
comprising: a blood collection container main body (¶ [0084] A closable system for producing PRP comprises: (a) a blood collection tube 1);
a plasma separation material stored in the blood collection container main body (¶ [0084], (d) a portion of separation gel 3); and
an aqueous solution stored in the blood collection container main body, a solute contained in the aqueous solution containing an anticoagulant (¶ [0089], FIG. 1 … an anticoagulant layer 4); and
a second solute other than an anticoagulant (¶ [0035], [0061], wherein the anticoagulant is selected from the group consisting of: buffer citrate, ACD, modified ACD (citric/citrate dextrose); ¶ [0089], The anticoagulant 4 is selected from the group consisting of: such as, but not limited to buffer citrate, ACD, modified ACD (citric/citrate dextrose)).
Esteron is silent regarding a total concentration of the solute in the aqueous solution and lacks an anticoagulant concentration being 50 mM or less. Walenciak discloses a method and device for collecting and stabilizing a biological sample, comprising a blood collection container (¶ [0002], [0012], [0016], [0023], [0026] Referring to FIG. 1 … a sample collection device 10);
comprising: a blood collection container main body (¶ [0026], FIG. 1 … sample collection device 10, which is provided with a stoppered-container 12);
an aqueous solution stored in the blood collection container main body, a solute contained in the aqueous solution containing an anticoagulant (¶ [0013] The anticoagulant according to the present invention should include about 5.6 to about 37.5 mM, preferably about 5.6 to about 10.1 mM, EDTA; ¶ [0027] The EDTA 14 may be pre-loaded into the container 12 of the present invention such that about 5.6 to about 37.5 mM, preferably about 5.6 to about 10.1 mM, EDTA is present when combined with the biological sample); and
a second solute other than an anticoagulant (¶ [0036] In addition, other components can be added to the admixture for the purpose of treating the biological sample … simple salts like salts of organic acids, alkali metal salts of halides, additional organic chelating agents, reducing agents, buffers, sugars);
the concentration of the anticoagulant in the aqueous solution being 50 mM or less (¶ [0032], A preferred embodiment of the device 10 is a 100 mm.times.16 mm PET tube having K3EDTA with an EDTA concentration of 8.1 mM);
the solute in the aqueous solution having a total concentration of 100 mM or more and 450 mM or less, or 1200 mM or more (¶ [0042], The other four tubes from Donor 2 were mixed the same way with 1.8 ml of a solution containing 0.9% NaCl and 1% Na.sub.2EDTA. That led to a molarity of about 8.1 mM EDTA. The other four tubes from Donor 3 were mixed the same way with 1.8 ml of a solution containing 0.9% NaCl and 7.5% Na.sub.2EDTA. That led to a molarity of about 37.5 mM EDTA).
Walenciak does not express the aqueous solution’s total concentration in molarity units. The molarity in mM (millimoles) has been calculated according to the equation:
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An aqueous NaCl (sodium chloride) solution of 0.9% has a molarity of approximately 154.7 mM according to the following calculation.
NaCl molarity 0.9% NaCl
Molar mass 58.443 g/mol
Density 1.0046 g/ml
% concentration
density (g/cm3)
molar mass (g/mol)
molarity (M)
molarity (mM)
0.7
1.0046
58.44
0.120
120.3
0.9
1.0046
58.44
0.155
154.7
1
1.0046
58.44
0.172
171.9
Walenciak’s aqueous solution contains both EDTA anticoagulant and 0.9% NaCl. Thus, Walenciak’s aqueous solution has a total solute concentration of approximately 10.1 mM EDTA + 154.7 mM NaCl = 164.8 mM, which overlaps the claimed range.
Walenciak selects a well-known anticoagulant for a blood collection container, and regulates the solution’s osmotic balance by adding enough NaCl to make it isotonic. Walenciak’s formula preserves and stabilizes DNA for later analysis (¶ [0002], [0011], [0018], [0019], [0027]). One would be motivated to modify Esteron with Walenciak’s anticoagulant concentration and total concentration to select a known alternative anticoagulant and optionally to improve its performance for preserving nucleic acids. Therefore, it would have been obvious to modify Esteron with Walenciak’s anticoagulant concentration and total concentration in order to use a widely known anticoagulant and optionally to preserve DNA.
Regarding claims 3-6, 8 and 17, Esteron discloses a blood collection container wherein the second solute includes an inorganic salt or a saccharide; wherein the second solute includes an inorganic salt, and the inorganic salt includes a sodium salt or a potassium salt; wherein the second solute includes a saccharide, and the saccharide includes glucose, sucrose, or trehalose (¶ [0035], [0061], wherein the anticoagulant is selected from the group consisting of: buffer citrate, ACD, modified ACD (citric/citrate dextrose); ¶ [0089], The anticoagulant 4 is selected from the group consisting of: such as, but not limited to buffer citrate, ACD, modified ACD (citric/citrate dextrose));
wherein the anticoagulant is EDTA, a metal salt of EDTA, heparin, a metal salt of heparin, or sodium citrate (¶ [0035], wherein the an anticoagulant is selected from the group consisting of: buffer citrate, ACD, modified ACD (citric/citrate dextrose); ¶ [0061], wherein the anticoagulant is selected from the group consisting of: buffer citrate, ACD, modified ACD (citric/citrate dextrose), heparinate salts, EDTA salts; ¶ [0089], The anticoagulant 4 is selected from the group consisting of: such as, but not limited to buffer citrate, ACD, modified ACD (citric/citrate dextrose), heparinate salts, EDTA salts);
wherein a specific gravity of the plasma separation material at 25° C. is 1.030 or more and 1.120 or less (¶ [0089], a separation gel 3 layer at a density of 1.04-1.09 gr/cm.sup.3; ¶ [0090], Such barrier-forming substance may be of the kind known per se, for example gel polymers. Gel polymers may, for example, be based on polyacrylic, polyolefin or polyester with a specific gravity in the range of about 1.04 to 1.09);
a method for separating plasma comprising: a step of collecting blood in the blood collection container according to claim 1, and a step of centrifuging the blood collection container in which the blood has been collected (¶ [0009], the tube is adapted such that, when containing cell suspension and centrifuged after treatment yields separation fractions; ¶ [0024], a system for obtaining platelet rich plasma (PRP) comprising: (a) a collection tube for collecting blood … the collection tube is adapted such that when containing the whole blood (5) and centrifuged after treatment yields separation fractions … a fourth fraction comprises platelets poor plasma (PPP) (8)).
Regarding claim 6 and the second solute that includes a sodium salt and glucose, Esteron calls for modified ACD (citric/citrate dextrose) (¶ [0035], [0061], [0089]). The modified ACD anticoagulant composition contains sodium citrate and dextrose.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Esteron and Walenciak in view of Josephs; Steven et al. (US 20210146030 A1).
Regarding claim 2, Esteron and Walenciak lack a total solute concentration in the claimed range. Josephs discloses a system and method for removal of immune inhibitors from plasma (¶ [0001], [0009], [0070], FIG. 1, system 10; ¶ [0137] In some embodiments, system 10 may be configured to facilitate reuse by alternating capture and dissociation steps);
wherein a total concentration of a solute in an aqueous solution is 250 mM or more and 390 mM or less, or 1200 mM or more and 6500 mM or less (¶ [0137], Agents that cause high salt concentrations, such as chaotropic agents or low pH may be effective dissociation agents. In order to dissociate the capture complex high salt, such as sodium chloride (300 mM-1,5M) … a salt solution may have a pH of approximately 7.2 and comprise either 500 mM NaOH, 2 mM EDTA and 50 mM Tris buffer, or 500 mM NaOH, 2 mM EDTA and 50 mM sodium phosphate).
Josephs incorporates a chaotropic salt or agent in an aqueous solution. One would be motivated to modify Esteron and Walenciak with Josephs’s total solute concentration since Walenciak calls for a chaotropic salt (¶ [0035] Additional additives may also be included with the EDTA 14 to help stabilize the biological sample 18. Examples of additional additives include cationic compounds, surfactants, chaotropic salts, ribonuclease inhibitors). Therefore, it would have been obvious to modify Esteron and Walenciak with Josephs’s total solute concentration in order to incorporate a chaotropic salt.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Esteron and Walenciak in view of Wegener; Christopher J. (US 20180168142 A1).
Regarding claim 7, Esteron discloses a blood collection container in which a predetermined amount of blood is collected (¶ [0024], (a) a collection tube for collecting blood (1); ¶ [0044], a method for producing of platelets rich plasma (PRP), the method comprising steps of: (a) obtaining a closable system for preparing platelet rich plasma (PRP) comprising: (i) a collection tube for collecting blood (1) … (c) filling the collection tube for collecting blood with whole blood sample; ¶ [0106], (c) filling the blood collection tube with whole blood sample 220).
Esteron and Walenciak are silent regarding an osmotic pressure of the mixed liquid. Wegener discloses a system and method for washing red blood cells (¶ [0002], [0006], [0020], [0021]);
comprising a blood collection container (¶ [0022] Preferably, however, the “blood” is provided as whole blood in a container which can be a blood processing, collection or storage container; ¶ [0027] In the study, as depicted in FIG. 2, whole blood units (n=13) were collected into CPD anticoagulant);
in which a predetermined amount of blood is collected (¶ [0021], providing a quantity of blood at step 201a, typically in a container; ¶ [0027] In the study, as depicted in FIG. 2, whole blood units (n=13) were collected into CPD anticoagulant);
wherein when physiological saline in an amount equivalent to a predetermined amount of blood collected in the blood collection container is collected in the blood collection container to obtain a mixed liquid in which the physiological saline and the aqueous solution are mixed, an osmotic pressure of the mixed liquid is 330 mOsm/L or more and 380 mOsm/L or less, or 440 mOsm/L or more and 1300 mOsm/L or less (¶ [0041] In accordance with a third aspect … the osmolarity value of the intermediate red blood cell product at the end of storage is 338-369 mOsm/L; ¶ [0043] In accordance with a fifth aspect … the osmolarity value of the intermediate red blood cell product at the end of storage is 392-479 mOsm/L).
Wegener selects an osmolarity value that minimizes damage to collected blood cells (¶ [0002] a wash media having a specific osmolarity value, to reduce hemolysis of cells; ¶ [0005], It is an aim of the wash process to maximize removal of undesirable extracellular components while minimizing cell hemolysis). One would be motivated to modify Esteron and Walenciak with Wegener’s osmolarity value to protect RBCs while processing them. A skilled artisan would have been able to modify Esteron and Walenciak with Wegener’s osmolarity value by adjusting the osmolarity of Esteron’s aqueous solution according to Wegener. Therefore, it would have been obvious to modify Esteron and Walenciak with Wegener’s osmolarity value in order to protect blood cells from lysis.
Claims 9-15 are rejected under 35 U.S.C. 103 as being unpatentable over Esteron and Walenciak in view of Okamoto; Ryusuke et al. (US 20180092806 A1).
Regarding claims 9-15, Esteron discloses that the composition for plasma separation contains an organic component including a resin; wherein the resin includes a petroleum resin, a cyclopentadiene-based resin, a polyester resin, or a (meth)acrylic resin (¶ [0090], Such barrier-forming substance may be of the kind known per se, for example gel polymers. Gel polymers may, for example, be based on polyacrylic, polyolefin or polyester);
wherein a specific gravity of the composition for plasma separation at 25° C. is 1.050 or more (¶ [0037], [0058], [0089] a separation gel 3 layer at a density of 1.04-1.09 gr/cm.sup.3).
Esteron and Walenciak lack an inorganic fine powder including fine powder silica, and are silent regarding the content of the powder silica. Okamoto discloses a serum- or plasma-separating composition (¶ [0001], [0012], [0024], [0030]);
wherein the composition for plasma separation contains an organic component having fluidity at 25° C. (¶ [0030] The serum- or plasma-separating composition of the present invention contains a resin composition having fluidity at normal temperature; ¶ [0031] The normal temperature used herein represents 20±5° C.); and
an inorganic fine powder (¶ [0053] The serum- or plasma-separating composition of the present invention contains a silica fine powder; ¶ [0054], natural silica and synthetic silica);
the organic component includes a resin (¶ [0030] The serum- or plasma-separating composition of the present invention contains a resin composition having fluidity at normal temperature … (meth)acrylic acid ester-based polymers and mixtures of a petroleum resin and a trimellitic acid-based plasticizer); and
the inorganic fine powder includes fine powder silica (¶ [0054] Examples of the silica fine powder include natural silica and synthetic silica);
wherein the fine powder silica includes hydrophilic silica (¶ [0054], Examples of such synthetic silica include hydrophilic silica and hydrophobic silica; ¶ [0059] As the hydrophobic silica, for example, hydrophobic silica produced by a gas phase process including AEROSIL series … REOLOSIL series … and WACKERHDK series … are easily available and used);
wherein a content of the hydrophilic silica is 0.01 wt % or more and 2.50 wt % or less in 100 wt % of the composition for plasma separation (¶ [0056] The total content of the hydrophilic silica and the hydrophobic silica … is preferably in the range of 1.40 to 2.50% by weight);
wherein the fine powder silica includes hydrophilic silica and hydrophobic silica (¶ [0054], Examples of such synthetic silica include hydrophilic silica and hydrophobic silica);
wherein the inorganic fine powder contains a second inorganic fine powder having a specific gravity larger than a specific gravity of the fine powder silica (¶ [0059], Any materials that can be kneaded homogeneously, which is not particularly limited to hydrophobic silica, may be used, such as alumina, glass fine powder, talc, kaolin, bentonite, titania, and zirconium).
Okamoto finely adjusts a separation composition’s thixotropy and specific gravity (¶ [0002], appropriate adjustment of the specific gravity of the serum- or plasma-separating composition enables centrifugation of a serum component or plasma component from whole blood using of a difference in specific gravities; ¶ [0051], addition of a large amount of the silica fine powder may be needed in order to adjust the specific gravity; ¶ [0055], hydrophilic silica and hydrophobic silica may be used in combination as appropriate in order to suitably adjust the thixotropy and the specific gravity). One would be motivated to modify Esteron and Walenciak with Okamoto’s powder silica content to obtain a desired thixotropy or specific gravity as called for by Esteron (¶ [0078], The tube containing cell suspension is adapted such that, when centrifuged after treatment yields separation fractions; ¶ [0090], Gel polymers may, for example, be based on polyacrylic, polyolefin or polyester with a specific gravity in the range of about 1.04 to 1.09; ¶ [0091], a centrifugation procedure 110 is performed on the basis of specific gravity). Therefore, it would have been obvious to modify Esteron and Walenciak with Okamoto’s powder silica content in order to adjust the separation composition’s thixotropy and specific gravity.
Claims 16 and 18-23 are rejected under 35 U.S.C. 103 as being unpatentable over Esteron and Walenciak in view of Fernando; M. Rohan (US 20190254273 A1).
Regarding claims 16 and 18-23, Esteron and Walenciak do not explicitly disclose a method for separating cell free nucleic acids or extracellular vesicles. Fernando discloses a method for stabilizing or analyzing a post-phlebotomy blood sample and diagnosing a disease (¶ [0008], [0011]-[0013], [0030] FIG. 2 represents a stabilizing composition tube 200);
comprising: a blood collection container (¶ [0030] FIG. 2 … The stabilizing composition tube 200 includes a tube 201, a lid 202, and a stabilizing composition 203);
wherein the blood collection container is configured to separate cell free nucleic acids or extracellular vesicles in blood (¶ [0070] An analyte may be an antibody, protein, lipid, DNA, mRNA microRNA, cfDNA, membrane receptors … An analyte may be associated with the interior of a target extracellular vesicle);
the method comprising: a step of collecting blood in the blood collection container (¶ [0034] The post-phlebotomy blood sample (not shown) may be collected from a human by venipuncture or other blood draw method. The post-phlebotomy blood sample may contain an analyte for analysis);
a step of centrifuging the blood collection container in which the blood has been collected to separate plasma from the blood (¶ [0046] In 503, the analyte is separated … via two stage centrifugation); and
a step of separating cell free nucleic acids or extracellular vesicles from the separated plasma (¶ [0003], analysis of analytes, such as antibodies or biomarkers including proteins, lipids, DNA, mRNA and microRNA present in extracellular vesicles; ¶ [0025] FIG. 10 represents a comparison of a protein concentration, a RNA concentration, and a DNA concentration determined from (1) a stabilizing composition contacted post-phlebotomy blood sample; ¶ [0070] An analyte may be an antibody, protein, lipid, DNA, mRNA microRNA, cfDNA, membrane receptors … An analyte may be associated with the interior of a target extracellular vesicle; ¶ [0071], The target extracellular vesicles may be associated with analytes; ¶ [0072] Background extracellular vesicles in a sample are extracellular vesicles produced by cells not associated with the condition of interest).
Fernando extracts analytes that correlate with various conditions or diseases and allow a caregiver to more accurately diagnose a patient (¶ [0032], the analysis of an analyte in the post-phlebotomy blood sample to yield a diagnosis may be conducted; ¶ [0044] FIG. 5 illustrates a method 500 of analyzing a post phlebotomy blood sample to determine the state of a condition of interest sufficient for diagnosis; ¶ [0049] In 504, the analyte is analyzed to determine a diagnosis … When chromosome aneuploidy is the condition of interest, for example trisomy 21, the determination will analyze the presence of an additional copy of chromosome 21 in the post-phlebotomy blood sample. When the condition of interest is the gender of an unborn baby, the determination will analyze the presence or absence of Y-chromosomal DNA in the post-phlebotomy blood sample. When the condition of interest is hyperglycemia or diabetes, the determination will analyze the glucose concentration of the post-phlebotomy blood sample). One would be motivated to modify Esteron and Walenciak with Fernando’s nucleic acid or extracellular vesicle extraction step to diagnose a larger number of conditions or diseases, and since Walenciak calls for preserving and studying nucleic acids (¶ [0011]). Therefore, it would have been obvious to modify Esteron and Walenciak by extracting nucleic acids or extracellular vesicles as taught by Fernando in order to diagnose conditions or diseases that correlate with known biomarkers.
Response to Arguments
The rejections of claims 14, 16 and 9-15 under 35 USC § 112 are withdrawn in view of the amendments filed 18 March 2026.
Applicant’s arguments filed 18 March 2026 regarding the rejection of claims 1-23 as amended, under 35 USC § 103 over Esteron, Turzi, Wegener, Okamoto and Fernando, have been fully considered and are persuasive. After further consideration, the amended claims are rejected on new grounds under 35 USC § 103 over Esteron, Walenciak, Josephs, Wegener, Okamoto and Fernando (see above).
Applicant’s arguments regarding Turzi have been considered but are moot because the reference is no longer cited in the current rejection.
Applicant submits that the combination of Esteron and Turzi fails to disclose the combination of "a solute contained in the aqueous solution containing an anticoagulant and a second solute other than an anticoagulant," "the concentration of the anticoagulant in the aqueous solution being 50 mM or less," and "the solute in the aqueous solution having a total concentration of 100 mM or more and 450 mM or less, or 1200 mM or more," according to the amended claims (remarks p. 7-8). Examiner responds that Esteron and Walenciak are cited in the new grounds of rejection as teaching all features of amended claim 1. Walenciak discloses a blood collection container and aqueous solution including EDTA and further solutes with a higher molarity, and which overlaps the claimed range.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Sumida, Emi et al. US 20050170327 A1
Monroe; Dougald et al. US 20130183655 A1
Åhl; Petra et al. US 20160045658 A1
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/Adam Marcetich/
Primary Examiner, Art Unit 3781
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