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 .
Response to Amendment
The Amendment filed 06/01/2026 has been entered. Claims 1-2 and 6-24 are pending in the application and will be examined herein. Claims 3-5 were previously cancelled. Claims 1, 15, and 21 are currently amended.
Status of Objections and Rejections
The objection to claims 1, 15, 21, 23-24 from the previous office action is withdrawn in view of Applicant's amendment. The objection to claims 2, 6-14, 16-20, and 22 is withdrawn based on dependency of all of the limitations of claims 1, 15, and 21.
The rejection of claim 21 under 35 U.S.C. 112(b) from the previous office action is withdrawn in view of Applicant's amendment. The rejection of claim 22 under 35 U.S.C. 112(b) is withdrawn based on dependency of all of the limitations of claim 21.
The rejection of claims 1-2, 6-7, 12-15, 18-20 under 35 U.S.C. 103 from the previous office action is withdrawn in view of Applicant's amendment. The rejection of claims 8, 9-11, 16-17, 21-23 22 are withdrawn based on dependency of all of the limitations of claims 1, 15, and 21, respectively.
New grounds of rejection under 35 U.S.C. 103 are necessitated by the amendments.
Response to Arguments
Applicant’s argument, see pages 11-16, filed 06/01/2026, with respect to amended claim(s) 1, 15, and 21, that Menon fails to teach the predetermined space and the absence of physical interference between successive filter layers has been considered but is moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant argues (pp. 12-16) that the amendment to the claims, which now requires a predetermined space between membranes, is discouraged and would render Menon’s asymmetric membrane inoperable for its intended purposes. Applicant references Menon in stating that the asymmetric Vivid Plasma Separation Membrane is within an arrangement where different membranes are stacked and mechanically pressed against each other and even peeled away due to lingering moisture. Applicant references the Examiner’s supporting reference from Pall Life Sciences (“VIVID Plasma Separation Membrane”) which states that the asymmetric membrane is intended to operate in intimate contact with a receiving medium and suggests there is a teaching away for using such a filter to satisfy the present claim limitations.
The Examiner respectfully disagrees.
The Examiner cites the Pall Life Sciences reference as corroborative evidence of a commercially available asymmetric membrane (second filter) with the claimed thickness and weight range and is not relied upon to teach the claimed second filter limitation. As discussed in the U.S.C. 103 rejection below, reference Burg now fulfills the claimed second filter thickness and weight range limitations. Menon merely provides VIVID Plasma Separation Membrane as an example asymmetric membrane ([0077]), and therefore, the suggested instructions from the Pall Life Sciences supporting reference (not fully incorporated by Menon) for using this particular filter is not broadly applied to all brands of asymmetric membrane. Menon even provides another asymmetric membrane example, a BTS Asymmetric Membrane ([0101]), that is not mentioned in the supporting reference. "A reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage” the use of asymmetric membranes in configurations having predetermined spacing while maintaining fluid communication (See MPEP 2145(X)(D)(1)). Applicant cites the Pall supporting reference in stating that “plasma does not freely flow from the bottom of the membrane and requires uniform contact with a receiving matrix for the plasma to be delivered to the test strip or device,” and concludes that having contact between different layers taught by Menon is critical and must be ensured; however, Pall also instructs to ensure that “the asymmetric structure of the membrane is not compressed or disturbed,” which can result from the suggested intimate contact. Nonetheless, the Examiner relies upon the embodiment of Menon’s invention described in paragraphs [0087] and shown in Fig. 2 where assembly 30 includes sample collection layer 32 which comprises an asymmetric membrane without mention of a particular brand. Paragraph [0091] explains that each of the three membranes (32, 34, and 36) in the assembly is within its own holder and structurally attachable/detachable to the surrounding membrane holders. This embodiment therefore, does not teach direct contact between the filters, yet still claims use of an asymmetric filter. Nonetheless, the present rejection relies upon reference Proulx for the teaching of providing a predetermined space and the absence of physical interference between successive filter layers, and Applicant has not established that incorporating such spacing into Menon’s device would render the asymmetric membrane inoperable.
Specification
The disclosure is objected to because of the following informalities:
Paragraph 0068 reads “the filter units should be as closer to each other as possible”. The applicant may correct this paragraph by replacing “closer” with “close”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2 and 6-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 1, lines 23 and 25 recite “the first filter unit and the second filter unit are detachably coupled to each other,” and “the second filter unit and the third filter unit are detachably coupled to each other,” yet the instant specification (US 20220168672 A1) does not mention detachability of the filter units, only that “the multi-layered filter may be disassembled to diagnose each component remaining in the filter,” (Abstract) and “to check the status of each filter unit” ([0089]). The instant specification does not provide a structure or mechanism by which the units are selectively attached and detached. It is unclear whether applicant had possession of a filter unit with multiple detachable filters at the effective filing date of the invention as the specification is silent to this limitation and does not list an example of such a filter that would satisfy this feature of the claim.
The rejection of claims 2, 6-14, and 23 are rejected based on dependency of all of the limitations of claims 1.
Regarding claim 15, lines 24-27 recite “the first filter unit and the second filter unit are detachably coupled to each other,” and “the second filter unit and the third filter unit are detachably coupled to each other,” yet the instant specification (US 20220168672 A1) does not mention detachability of the filter units, only that “the multi-layered filter may be disassembled to diagnose each component remaining in the filter,” (Abstract) and “to check the status of each filter unit” ([0089]). The instant specification does not provide a structure or mechanism by which the units are selectively attached and detached. It is unclear whether applicant had possession of a filter unit with multiple detachable filters at the effective filing date of the invention as the specification is silent to this limitation and does not list an example of such a filter that would satisfy this feature of the claim.
The rejection of claims 16-20, and 24 are rejected based on dependency of all of the limitations of claim 15.
Regarding claim 21, lines 22 and 24-26 recite “the first filter unit and the second filter unit are detachably coupled to each other,” “the second filter unit and the third filter unit are detachably coupled to each other,” and “the third filter unit and the fourth filter unit are detachably coupled to each other,” yet the instant specification (US 20220168672 A1) does not mention detachability of the filter units, only that “the multi-layered filter may be disassembled to diagnose each component remaining in the filter,” (Abstract) and “to check the status of each filter unit” ([0089]). The instant specification does not provide a structure or mechanism by which the units are selectively attached and detached. It is unclear whether applicant had possession of a filter unit with multiple detachable filters at the effective filing date of the invention as the specification is silent to this limitation and does not list an example of such a filter that would satisfy this feature of the claim.
The rejection of claim 22 is rejected based on dependency of all of the limitations of claim 21.
Regarding claim 23, lines 6-8 recite “the fourth filter unit is…detachably connected to the third filter unit,” yet the instant specification (US 20220168672 A1) does not mention detachability of the filter units, only that “the multi-layered filter may be disassembled to diagnose each component remaining in the filter,” (Abstract) and “to check the status of each filter unit” ([0089]). The instant specification does not provide a structure or mechanism by which the units are selectively attached and detached. It is unclear whether applicant had possession of a filter unit with multiple detachable filters at the effective filing date of the invention as the specification is silent to this limitation and does not list an example of such a filter that would satisfy this feature of the claim.
Regarding claim 24, lines 6-8 recite “the fourth filter unit is…detachably connected to the third filter unit,” yet the instant specification (US 20220168672 A1) does not mention detachability of the filter units, only that “the multi-layered filter may be disassembled to diagnose each component remaining in the filter,” (Abstract) and “to check the status of each filter unit” ([0089]). The instant specification does not provide a structure or mechanism by which the units are selectively attached and detached. It is unclear whether applicant had possession of a filter unit with multiple detachable filters at the effective filing date of the invention as the specification is silent to this limitation and does not list an example of such a filter that would satisfy this feature of the claim.
Claim Interpretation
The claims contain limitations which are directed to intended uses or capabilities of the claimed invention. These limitations are only given patentable weight to the extent which effects the structure of the claimed invention. Please see MPEP 2114. Note that functional limitations are emphasized in italics herein.
Claim Rejections - 35 USC § 103
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 6-7, 12-15, 18-20, and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Menon et al. (US 20140273058 A1), as evidenced by Pall Life Sciences (“Vivid™ Plasma Separation Membrane; 2009), in view of Marble et al. (US 20130184446 A1), Lee et al. (US 20150090674 A1), Burg et al. (US 20140263059 A1) and Proulx et al. (WO 0032290 A1, see attached English translation).
Regarding claim 1, Menon teaches a filter (an integrated membrane assembly 30; [0087]; Fig. 2) comprising:
a second filter unit (a sample collection layer 32 (alternatively referred to as a cell collection layer; [0087]; Fig. 2) having a pore size of 0.05-1 um (“The sample collection layer 32 comprises an asymmetric membrane,” wherein the “asymmetric membrane [has a]…pore size of 0.2 .mu.m.; [0087][0082]; Fig. 3), the second filter unit being configured to separate and retain a second set of blood components from the first passing -through stream, and let through a second passing-through stream, the second set of blood components including blood platelet or exosome (“The porosity of the membrane was carefully selected in order to trap and remove cell/cellular debris while allowing nucleic acid species and proteins to flow through,” wherein cell is defined to include “platelets”; [0100][0069]),
a third filter unit (“a second layer for protein adsorption,” or “a protein adsorption layer 34”; Abstract; [0087]; Fig. 2) configured to separate and retain a third set of blood components, and let through a third passing-through stream from the second passing-through stream, the third set of blood components including proteins (a protein adsorption layer 84 designed to selectively remove proteins from the cell free flow through, wherein the third passing-through stream contained nucleic acid species; [0100]); and
wherein the second and third filter units are sequentially arranged such that the whole blood sample passes through the second unit and third unit in sequence (sequence the filtering process to first filter cells and then proteins to avoid degradation of the nucleic acids; [0026]; See order of layers 32, 34, and 36 of Figs. 2-3),
wherein the second filter unit and the third filter unit are detachably coupled to each other (“each holder 64 is capable of removably engaging at least one adjacent holder 64,” wherein each holder 64 encases a separate filter 32 and 34; [0091]; Figs. 2-3),
wherein the second filter unit and the third filter unit are configured to be disassembled after filtering (This pie-shaped design of the membrane 32, 34, 36 allows a user to easily separate sections of each of the membrane 32, 34, 36 for easy partial sample analysis; [0092]; Fig. 3) such that the second set of blood components retained at the second filter unit are collected for a second further test or experiment pertaining to the second set of blood components, and a third set of blood components retained at the third filter unit are collected for a third further test or experiment pertaining to the third set of blood components (The multi-layered filter taught by Menon is functionally capable of performing these analysis steps since the each of the layers can be disassembled for partial sample analysis ([0092]; Fig. 3)).
Menon fails to teach:
a first filter unit, having a pore size of 5-15 um, a thickness of 500-1500 um, and a weight of 100-400 gram/m2, the first filter unit being configured to separate and retain a first set of blood components from a whole blood sample and let through a first passing-through stream, the first set of blood components including blood cells,
the second filter, having a thickness of 100-1000 um, and a weight of 100-300 gram/m2 (emphasis added),
a third filter unit having a pore size of 0.003-0.01 um (emphasis added), and
a first and second predetermined space with no physical interference therebetween that separates the first and second filtration units and the second and third filtration units, respectively,
wherein the second filter unit has a pore size smaller than the pore size of the first filter unit, and the third filter unit has a pore size smaller than the pore size of the second filter unit.
Marble teaches:
a first filter unit, having a pore size of 5-15 um, (the first size-exclusion filter has a pore size of about 10 µm; [0022]), the first filter unit being configured to separate and retain a first set of blood components from a whole blood sample and let through a first passing-through stream (excludes passage therethrough of lymphocytes, monocytes, neutrophils, eosinophils, and basophils; [0015]) the first set of blood components including blood cells, (the sample comprises whole blood; [0013])
a third filter unit having a pore size of 0.01 um (“the shearing filter has a pore size of about 0.01-0.4 µm,” such that “microorganism nucleic acid is released”;[0022],[0015]).
the second filter unit has a pore size smaller than the pore size of the first filter unit, and the third filter unit has a pore size smaller than the pore size of the second filter unit (This limitation is fulfilled by the prior art in that the first filter is 10 µm, the second filter is 0.2 µm (Menon), and the third filter is 0.01 µm (See overlapping ranges statement below)).
Marble is considered to be analogous to the claimed invention because it is in the same field of endeavor for a multi-layered filter for separating blood components. Primary reference, Menon, teaches the third layer (protein adsorption layer) allows nucleic acids RNA/DNA to pass through ([0083]), while Marble uses a shearing filter to release nucleic acids using a pore size of 0.01-0.4 µm ([0015]). Menon teaches the second layer (sample collection layer) to be an 0.2 µm asymmetric membrane comprising larger pores on an upstream portion and smaller pores on a downstream portion, where the larger upstream pores act as a pre-filter while the smaller downstream pores serve as an absolute cut-off layer, enabling the efficient captures of cells while reducing clogging ([0085]). 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 multi-layered filter taught by Menon to incorporate the teachings of Marble by adding a first filter unit above the second filter unit, having a pore size of 5-15 um, separating blood cells from a whole blood sample, and adding 0.01 µm pores to the third filter, because this would reduce clogging in the subsequent layers by removing bulk whole blood cells early and provide an additional size exclusion separation technique to recover nucleic acids, and this involves combining prior art elements according to known methods to yield predictable results (See MPEP 2143(I)(A)).
Modified Menon fails to teach the third filter unit has a pore size of 0.003-0.01 um (emphasis added). Modified Menon instead teaches that the third filter has a pore size of about 0.01 μm which is a partial overlap (Marble, [0015]) of the claimed range. Primary reference, Menon, teaches a protein-removal layer in a stacked filter assembly (See Fig. 2) and explicitly states that each layer is a porous membrane ([0088]) used to deplete proteins so nucleic acids are preserved for downstream analysis (Abstract). One of ordinary skill in the art seeking to ensure protein separation (the function of the third filter as stated in the abstract of the instant publication US20220168672A1) would naturally look to known pore-size implementations for fine cutoffs. Marble discloses a downstream filter stage with pores as small as about 0.01 um within the same kind of multi-stage, blood sample filtration stack as Menon, demonstrating the feasibility and predictability of using micro to sub-micron cutoffs in this context. Pore size is a result-effective variable governing what passes or what is retained. Because Marble touches the claimed band at 0.01 um, modifying the filter taught by Menon by selecting a 0.01 um filter, and then routinely optimizing this result-effective variable to slightly below (0.003-0.01) would have been obvious to one having an ordinary skill in the art before the effective filing date of the invention (MPEP 2144.05(I)).
Modified Menon fails to teach the first filter has a thickness of 500-1500 um, and a weight of 100-400 gram/m2 ,
the second filter has a thickness of 100-1000 um, and a weight of 100-300 gram/m2 (emphasis added), and
a first and second predetermined space with no physical interference therebetween that separates the first and second filtration units and the second and third filtration units, respectively.
Lee teaches a filter having a thickness of 500-1500 um (“The filter member may have a thickness in a range from about 0.8 to about 1.2 mm,” wherein this equates to a range of 800-1200um; [0029]), and a weight of 100-400 gram/m2 (The filter member may have a weight per surface area (or a basis weight) in a range from about…70 to about 120 g/m.sup.2; [0029]).
Lee is considered to be analogous to the claimed invention because it is in the same field of endeavor for a multi-layered filter for separating blood components. Primary reference, Menon expresses a desire to collect blood cells without lysis ([0101]). Secondary reference Marble teaches staged size-exclusion filters with the first filter dimensioned for whole-cell capture ([0015]). Lee teaches that blood filter members having a thickness and weight per surface area in a particular range provide high plasma recovery while preventing hemolysis ([0028][0029]). It would have been advantageous to select Lee’s disclosed thickness and weight for the first filter of Menon in view of Marble to ensure durability, capacity, and reduced cell lysis, as both Lee and Menon stress the importance of avoiding red blood cell rupture. 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 multi-layered filter taught by Menon in view of Marble to incorporate the teachings of Lee by adding a first filter, having a thickness of 500-1500 um and a weight of 100-400 gram/m2 because this would “reduce the occurrence of hemolysis of corpuscles including erythrocytes” (Lee, [0028]). The overlapping filter weight range between the teaching of Lee and the instant claim is a matter of optimizing a routine result-effective variable to yield the predictable outcome of a lower amount of lysed cells (See MPEP 2144.05). 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 chosen these filter characteristics so as to achieve such a benefit.
Modified Menon fails to teach the second filter has a thickness of 100-1000 um, and a weight of 100-300 gram/m2 (emphasis added), and
a first and second predetermined space with no physical interference therebetween that separates the first and second filtration units and the second and third filtration units, respectively.
Burg teaches a filter, having a thickness of 100-1000 um (asymmetric… polysulfone membrane…the separation membrane thickness…about 400 .mu.m; [0039]).
Burg is considered to be analogous to the claimed invention because it is in the same field of endeavor for separation of plasma from whole blood using filtration membranes. Menon employs an asymmetric membrane to reduce clogging ([0082]) while Burg aims to reduce clogging by optimizing the physical characteristics of an asymmetric membrane including thickness and surface area ([0039]). Burg therefore recognizes membrane dimensions as result-effective variables that are selected to achieve the desired plasma separation performance. Also, since the claimed membrane weight is a direct function of membrane thickness and void volume, optimizing these parameters to achieve an appropriate weight would have been no more than the routine optimization of result-effective variables (See MPEP 2144.05(II)(B)). This conclusion is further supported by Menon’s identification of the commercially available Pall Vivid Plasma Separation membrane, whose published specifications permit calculation of a basis weight of approximately 161 g/m2 (this weight is calculated using a thickness of 330 um, 1.24 g/cm3 density of polysulfone, and a void volume of 20ul/cm2; see p. 2, col. 1, para. 2, ll. 7-8 of the attached product data sheet for Pall Life Sciences. 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 multi-layered filter taught by Menon in view of Marble and Lee to incorporate the teachings of Burk by optimizing these recognized variables, including a membrane a thickness of 100-1000 um, and a corresponding weight of 100-300 gram/m2, because it would obtain the desired filtration performance, and this involves routine experimentation to reach another workable product (See MPEP 2144.05(II)(B)).
Modified Menon fails to teach a first and second predetermined space with no physical interference therebetween that separates the first and second filtration units and the second and third filtration units, respectively.
Proulx teaches a first and second predetermined space with no physical interference therebetween that separates the first and second filtration units and the second and third filtration units, respectively (“A plurality of stacks of filter sheets 28 are positioned within housing 12 separated by annular spacers 27 throughout the height of the housing 12,” with “annular spaces 27 having an open central volume”; p. 13, ll. 4-6; Fig. 1A)(P. 7, ll. 5-21 explains that the predetermined thickness of the spacer is based upon the thickness of the filter to achieve the desired result and is therefore a predetermined space)(Paragraph [0068] of the instant publication states that “no physical interference, such as external pressure, [[that]] damages the basic structure of the filters,” and since Proulx explains that “The spacers provide a means for substantially reducing the compressibility of the depth filter during use under the pressure of feed fluid,” this limitation is satisfied by the prior art; Proulx, p. 7, ll. 11-13).
Proulx is considered to be analogous to the claimed invention because it is in the same field of endeavor for the separation of blood components from whole blood using filtration membranes (p. 10, ll. 18-22). Both Menon and Proulx teach a stacked filter arrangement for separating blood components from whole blood, and Proulx explains that filters are undesirably susceptible to compression under fluid pressure depending upon the filter thickness (p. 3, ll. 14-18). Proulx further explains that this compression increases the likelihood of plugging, shortens the filter’s useful life, and requires higher operating pressure to maintain flow; this creates channeling which allows fluid to bypass the filter bed so that larger particles are not effectively removed (p. 3, ll. 18-27). As a solution, Proulx uses spacers to reduce this compression by scaling the spacer thickness using a ratio involving the filter thickness (p. 4, ll. 25-30; p. 7, ll. 5-20). Finally, Proulx notes that the filters are retained within housing that is free of open void space and the spacers still allow fluid to pass therethrough, providing a reasonable expectation of successful for the appropriate capillary forces to take affect even when using filters that require intimate contact. 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 multi-layered filter taught by Menon in view of Marble, Lee, and Burk to incorporate the teachings of Proulx by including a spacer between each filter, because they would aid in achieving the desired filtration performance, and this involves combining prior art elements according to known methods to yield predictable results. (See MPEP 2143(I)(A)).
Regarding claim 2, Modified Menon teaches the filter according to claim 1, wherein the whole blood sample passed through the third filter unit includes at least one of amino acids, bases and various metabolites (the multi-layer filter taught by modified Menon is functionally capable of passing of amino acids, bases or various [metabolites] through the third filter. Menon states that the hydrophobic C18 filter of the protein adsorption layer allows nucleic acids to remain in the sample flow and are stabilized downstream in the fourth layer ([0079]). Molecules smaller than nucleic acids lacking the hydrophobic portions capable of interacting with the C18, such as those mentioned in the claim limitation, would naturally pass through the third filter).
Regarding claim 6, Modified Menon teaches the filter according to claim 1, wherein the filter is configured to separate the whole blood sample administrated in an amount of 20- 100 uL (sample volumes as small as 5 .mu.l up to 150 .mu.l of whole blood.; [0106]).
Although modified Menon teaches a slightly broader range than the instant claim, the selection of a more narrow whole blood sample in an amount 20-100 ul would have been a matter of routine optimization of a result-effective variable (See MPEP 2144.05(I)). It would have been obvious before the effective filing date of the claimed invention to have chosen this range of whole blood volume so as to yield the predictable outcome of a better separation of blood sample components.
Regarding claim 7, Modified Menon teaches a disease diagnosis kit (an integrated membrane assembly 30; [0087]; Fig. 2) configured to measure blood P-selectin by using the filter according to claim 1 (The multi-layered filter taught by modified Menon is functionally capable of measuring blood P-selectin since the protein adsorption layer of Menon has a pore size small enough to filter proteins and is highly hydrophobic which can bind to hydrophobic P-selectin. Subsequent measuring can ensue by further observation).
Regarding claim 12, Modified Menon teaches the filter of claim 1.
Modified Menon fails to teach the third filter unit further includes additional filter unit according to a size of the protein to be separated and retained. However primary reference, Menon, teaches the second layer to be an asymmetric membrane comprising larger pores on an upstream portion and smaller pores on a downstream portion, where the larger upstream pores act as a pre-filter while the smaller downstream pores serve as an absolute cut-off layer ([0085]). It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention to have substituted the membrane used in the protein adsorption layer with an asymmetric membrane for the expectation of predictable results in order to reduce clogging in the subsequent layers, a technique that is well-known in the art ([0085]) (See MPEP 2143(I)(B)).
Regarding claim 13, Modified Menon teaches the filter of claim 1, wherein the first filter unit is made of a material selected from a group of natural fibers (Any suitable size-exclusion filter can be used…an example…cellulose acetate size exclusion filter; Marble, [0038]).
Regarding claim 14, Modified Menon teaches the filter of claim 1, wherein the third filter unit is made of a material with low affinity and adsorption for nucleic acids (The protein adsorption layer 14 comprises a membrane conjugated to an 18-mer hydrocarbon chain (C18)… enables hydrophilic molecules, such as RNA/DNA, to flow through the layer 14 for subsequent preservation of protein-free nucleic acids; Menon, [0083]) or proteins .
Regarding claim 15, Menon teaches a method of separating a plurality of blood components from a whole blood sample by passing the whole blood sample through (separate of classes of biomolecules such as cells, proteins and nucleic acids (DNA/RNA) fully preserved from whole blood; [0019])(The top side 20 is exposed to whole blood while the bottom side 22 is exposed to the flow-through processed sample; [0075]; Fig. 1)(the layers 12, 14, 16 are stacked and pressed together as a single unit ; [0085]; Fig. 1; filters 32, 34, and 36 of Fig. 2) through a multi-layered filter (an integrated membrane assembly 30; [0087]; Fig. 2), the method comprising:
separating and retaining a second set of blood components through a second filter unit of the multi-layered filter, letting through a second passing-through stream, wherein the second filter unit has a pore size of 0.05-1 um (“The sample collection layer 32 comprises an asymmetric membrane,” wherein the “asymmetric membrane [has a]…pore size of 0.2 .mu.m.; [0087][0082]; Fig. 3), and wherein the second set of blood components includes blood platelet or exosome (“The porosity of the membrane was carefully selected in order to trap and remove cell/cellular debris while allowing nucleic acid species and proteins to flow through,” wherein cell is defined to include “platelets”; [0100][0069]), and
separating and retaining a third set of blood components from the second passing-through stream through a third filter unit of the multi-layered filter, letting through a third passing-through stream, and wherein the third set of blood components includes proteins, (a protein adsorption layer 84 designed to selectively remove proteins from the cell free flow through, wherein the third passing-through stream contained nucleic acid species; [0100]); and
wherein the second and third filter units are sequentially arranged such that the whole blood sample passes through the second unit and third unit in sequence (sequence the filtering process to first filter cells and then proteins to avoid degradation of the nucleic acids; [0026]; See order of layers 32, 34, and 36 of Figs. 2-3),
wherein the second filter unit and the third filter unit are detachably coupled to each other (“each holder 64 is capable of removably engaging at least one adjacent holder 64,” wherein each holder 64 encases a separate filter 32 and 34; [0091]; Figs. 2-3),
wherein the second filter unit and the third filter unit are disassembled after the separating and retaining of the third set of blood components, wherein after second filter unit and the third filter unit are disassembled, the second set of blood components retained at the second filter unit are collected for a second further test or experiment pertaining to the second set of blood components, and the third set of blood components retained at the third filter unit are collected for a third further test or experiment pertaining to the third set of blood components (See the results of total protein concentration and RNA post-loading in Figs. 9-12)(This pie-shaped design of the membrane 32, 34, 36 allows a user to easily separate sections of each of the membrane 32, 34, 36 for easy partial sample analysis, leaving other sections of the membrane available for analysis at a later time or for concurrent analysis; [0092]).
Menon fails to teach:
a first filter unit, having a pore size of 5-15 um, a thickness of 500-1500 um, and a weight of 100-400 gram/m2, the first filter unit being configured to separate and retain a first set of blood components from a whole blood sample and let through a first passing-through stream, the first set of blood components including blood cells,
the second filter, having a thickness of 100-1000 um, and a weight of 100-300 gram/m2 (emphasis added),
a third filter unit having a pore size of 0.003-0.01 um (emphasis added), and
a first and second predetermined space with no physical interference therebetween that separates the first and second filtration units and the second and third filtration units, respectively,
wherein the second filter unit has a pore size smaller than the pore size of the first filter unit, and the third filter unit has a pore size smaller than the pore size of the second filter unit.
Marble teaches:
a first filter unit, having a pore size of 5-15 um, (the first size-exclusion filter has a pore size of about 10 µm; [0022]), the first filter unit being configured to separate and retain a first set of blood components from a whole blood sample and let through a first passing-through stream (excludes passage therethrough of lymphocytes, monocytes, neutrophils, eosinophils, and basophils; [0015]) the first set of blood components including blood cells, (the sample comprises whole blood; [0013])
a third filter unit having a pore size of 0.01 um (“the shearing filter has a pore size of about 0.01-0.4 µm,” such that “microorganism nucleic acid is released”;[0022],[0015]).
the second filter unit has a pore size smaller than the pore size of the first filter unit, and the third filter unit has a pore size smaller than the pore size of the second filter unit (This limitation is fulfilled by the prior art in that the first filter is 10 µm, the second filter is 0.2 µm (Menon), and the third filter is 0.01 µm (See overlapping ranges statement below)).
Marble is considered to be analogous to the claimed invention because it is in the same field of endeavor for a multi-layered filter for separating blood components. Primary reference, Menon, teaches the third layer (protein adsorption layer) allows nucleic acids RNA/DNA to pass through ([0083]), while Marble uses a shearing filter to release nucleic acids using a pore size of 0.01-0.4 µm ([0015]). Menon teaches the second layer (sample collection layer) to be an 0.2 µm asymmetric membrane comprising larger pores on an upstream portion and smaller pores on a downstream portion, where the larger upstream pores act as a pre-filter while the smaller downstream pores serve as an absolute cut-off layer, enabling the efficient captures of cells while reducing clogging ([0085]). 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 multi-layered filter taught by Menon to incorporate the teachings of Marble by adding a first filter unit above the second filter unit, having a pore size of 5-15 um, separating blood cells from a whole blood sample, and adding 0.01 µm pores to the third filter, because this would reduce clogging in the subsequent layers by removing bulk whole blood cells early and provide an additional size exclusion separation technique to recover nucleic acids, and this involves combining prior art elements according to known methods to yield predictable results (See MPEP 2143(I)(A)).
Modified Menon fails to teach the third filter unit has a pore size of 0.003-0.01 um (emphasis added). Modified Menon instead teaches that the third filter has a pore size of about 0.01 μm which is a partial overlap (Marble, [0015]) of the claimed range. Primary reference, Menon, teaches a protein-removal layer in a stacked filter assembly (See Fig. 2) and explicitly states that each layer is a porous membrane ([0088]) used to deplete proteins so nucleic acids are preserved for downstream analysis (Abstract). One of ordinary skill in the art seeking to ensure protein separation (the function of the third filter as stated in the abstract of the instant publication US20220168672A1) would naturally look to known pore-size implementations for fine cutoffs. Marble discloses a downstream filter stage with pores as small as about 0.01 um within the same kind of multi-stage, blood sample filtration stack as Menon, demonstrating the feasibility and predictability of using micro to sub-micron cutoffs in this context. Pore size is a result-effective variable governing what passes or what is retained. Because Marble touches the claimed band at 0.01 um, modifying the filter taught by Menon by selecting a 0.01 um filter, and then routinely optimizing this result-effective variable to slightly below (0.003-0.01) would have been obvious to one having an ordinary skill in the art before the effective filing date of the invention (MPEP 2144.05(I)).
Modified Menon fails to teach the first filter has a thickness of 500-1500 um, and a weight of 100-400 gram/m2 ,
the second filter has a thickness of 100-1000 um, and a weight of 100-300 gram/m2 (emphasis added), and
a first and second predetermined space with no physical interference therebetween that separates the first and second filtration units and the second and third filtration units, respectively.
Lee teaches a filter having a thickness of 500-1500 um (“The filter member may have a thickness in a range from about 0.8 to about 1.2 mm,” wherein this equates to a range of 800-1200um; [0029]), and a weight of 100-400 gram/m2 (The filter member may have a weight per surface area (or a basis weight) in a range from about…70 to about 120 g/m.sup.2; [0029]).
Lee is considered to be analogous to the claimed invention because it is in the same field of endeavor for a multi-layered filter for separating blood components. Primary reference, Menon expresses a desire to collect blood cells without lysis ([0101]). Secondary reference Marble teaches staged size-exclusion filters with the first filter dimensioned for whole-cell capture ([0015]). Lee teaches that blood filter members having a thickness and weight per surface area in a particular range provide high plasma recovery while preventing hemolysis ([0028][0029]). It would have been advantageous to select Lee’s disclosed thickness and weight for the first filter of Menon in view of Marble to ensure durability, capacity, and reduced cell lysis, as both Lee and Menon stress the importance of avoiding red blood cell rupture. 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 multi-layered filter taught by Menon in view of Marble to incorporate the teachings of Lee by adding a first filter, having a thickness of 500-1500 um and a weight of 100-400 gram/m2 because this would “reduce the occurrence of hemolysis of corpuscles including erythrocytes” (Lee, [0028]). The overlapping filter weight range between the teaching of Lee and the instant claim is a matter of optimizing a routine result-effective variable to yield the predictable outcome of a lower amount of lysed cells (See MPEP 2144.05). 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 chosen these filter characteristics so as to achieve such a benefit.
Modified Menon fails to teach the second filter has a thickness of 100-1000 um, and a weight of 100-300 gram/m2 (emphasis added), and
a first and second predetermined space with no physical interference therebetween that separates the first and second filtration units and the second and third filtration units, respectively.
Burg teaches a filter, having a thickness of 100-1000 um (asymmetric… polysulfone membrane…the separation membrane thickness…about 400 .mu.m; [0039]).
Burg is considered to be analogous to the claimed invention because it is in the same field of endeavor for separation of plasma from whole blood using filtration membranes. Menon employs an asymmetric membrane to reduce clogging ([0082]) while Burg aims to reduce clogging by optimizing the physical characteristics of an asymmetric membrane including thickness and surface area ([0039]). Burg therefore recognizes membrane dimensions as result-effective variables that are selected to achieve the desired plasma separation performance. Also, since the claimed membrane weight is a direct function of membrane thickness and void volume, optimizing these parameters to achieve an appropriate weight would have been no more than the routine optimization of result-effective variables (See MPEP 2144.05(II)(B)). This conclusion is further supported by Menon’s identification of the commercially available Pall Vivid Plasma Separation membrane, whose published specifications permit calculation of a basis weight of approximately 161 g/m2 (this weight is calculated using a thickness of 330 um, 1.24 g/cm3 density of polysulfone, and a void volume of 20ul/cm2; see p. 2, col. 1, para. 2, ll. 7-8 of the attached product data sheet for Pall Life Sciences. 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 multi-layered filter taught by Menon in view of Marble and Lee to incorporate the teachings of Burk by optimizing these recognized variables, including a membrane a thickness of 100-1000 um, and a corresponding weight of 100-300 gram/m2, because it would obtain the desired filtration performance, and this involves routine experimentation to reach another workable product (See MPEP 2144.05(II)(B)).
Modified Menon fails to teach a first and second predetermined space with no physical interference therebetween that separates the first and second filtration units and the second and third filtration units, respectively.
Proulx teaches a first and second predetermined space with no physical interference therebetween that separates the first and second filtration units and the second and third filtration units, respectively (“A plurality of stacks of filter sheets 28 are positioned within housing 12 separated by annular spacers 27 throughout the height of the housing 12,” with “annular spaces 27 having an open central volume”; p. 13, ll. 4-6; Fig. 1A)(P. 7, ll. 5-21 explains that the predetermined thickness of the spacer is based upon the thickness of the filter to achieve the desired result and is therefore a predetermined space)(Paragraph [0068] of the instant publication states that “no physical interference, such as external pressure, [[that]] damages the basic structure of the filters,” and since Proulx explains that “The spacers provide a means for substantially reducing the compressibility of the depth filter during use under the pressure of feed fluid,” this limitation is satisfied by the prior art; Proulx, p. 7, ll. 11-13).
Proulx is considered to be analogous to the claimed invention because it is in the same field of endeavor for the separation of blood components from whole blood using filtration membranes (p. 10, ll. 18-22). Both Menon and Proulx teach a stacked filter arrangement for separating blood components from whole blood, and Proulx explains that filters are undesirably susceptible to compression under fluid pressure depending upon the filter thickness (p. 3, ll. 14-18). Proulx further explains that this compression increases the likelihood of plugging, shortens the filter’s useful life, and requires higher operating pressure to maintain flow; this creates channeling which allows fluid to bypass the filter bed so that larger particles are not effectively removed (p. 3, ll. 18-27). As a solution, Proulx uses spacers to reduce this compression by scaling the spacer thickness using a ratio involving the filter thickness (p. 4, ll. 25-30; p. 7, ll. 5-20). Finally, Proulx notes that the filters are retained within housing that is free of open void space and the spacers still allow fluid to pass therethrough, providing a reasonable expectation of successful for the appropriate capillary forces to take affect even when using filters that require intimate contact. 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 multi-layered filter taught by Menon in view of Marble, Lee, and Burk to incorporate the teachings of Proulx by including a spacer between each filter, because they would aid in achieving the desired filtration performance, and this involves combining prior art elements according to known methods to yield predictable results. (See MPEP 2143(I)(A)).
Regarding claim 18, Modified Menon teaches the method of claim 15.
Modified Menon fails to teach the third filter unit further includes additional filter unit according to a size of the protein to be separated. However primary reference, Menon, teaches the second layer to be an asymmetric membrane comprising larger pores on an upstream portion and smaller pores on a downstream portion, where the larger upstream pores act as a pre-filter while the smaller downstream pores serve as an absolute cut-off layer ([0085]). It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention to have substituted the membrane used in the protein adsorption layer with an asymmetric membrane for the expectation of predictable results in order to reduce clogging in the subsequent layers ([0085]).
Regarding claim 19, Modified Menon teaches the method of claim 15, wherein the first filter unit is made of a material selected from a group of natural fibers (Any suitable size-exclusion filter can be used…an example…cellulose acetate size exclusion filter; Marble, [0038).
Regarding claim 20, Modified Menon teaches the method of claim 15, wherein the third filter unit is made of a material with low affinity and adsorption for nucleic acids (The protein adsorption layer 14 comprises a membrane conjugated to an 18-mer hydrocarbon chain (C18)…enables hydrophilic molecules, such as RNA/DNA, to flow through the layer 14 for subsequent preservation of protein-free nucleic acids; [0083]) or proteins.
Regarding claim 23, Modified Menon teaches the filter of claim 1, further comprising:
a fourth filter unit, made of an affinity-facilitating material, (DNA and RNA bind to silica matrices with high affinity; Menon, [0088]), separating and retaining a fourth set of blood components from the third passing-through stream, letting through a remaining passing-through stream, wherein the fourth set of blood components include small protein or nucleic acid components (the multi-layer filter taught by modified Menon is functionally capable of passing of amino acids, bases or various [metabolites] through the third filter. Menon states that the hydrophobic C18 filter of the protein adsorption layer allows nucleic acids to remain in the sample flow and are stabilized downstream in the fourth layer ([0079]),
wherein the fourth filter unit is stacked behind the third filter unit in a direction of the whole blood sample passes through the filter (See the sequential arrangement of filters 34-36 in Fig. 2 of Menon), and is detachably connected to the third filter unit (“each holder 64 is capable of removably engaging at least one adjacent holder 64,” wherein each holder 64 encases a separate filter 32-36; Menon, [0091]; Figs. 2-3) with a predetermined space separating therebetween (A plurality of stacks of filter sheets 28 are positioned within housing 12 separated by annular spacers 27 throughout the height of the housing 12; Proulx, p. 13, ll. 4-6) and disassembled after filtering, wherein after the fourth filter unit is disassembled after filtering the whole blood sample, the fourth set of blood components retained at the fourth filter unit are collected for a fourth further test or experiment pertaining to the fourth set of blood components (See the results of total protein concentration and RNA post-loading in Figs. 9-12 of Menon)(This pie-shaped design of the membrane 32, 34, 36 allows a user to easily separate sections of each of the membrane 32, 34, 36 for easy partial sample analysis, leaving other sections of the membrane available for analysis at a later time or for concurrent analysis; Menon, [0092]), or for a purpose of preservation or transportation via one or more sample-preservation methods, and the remaining passing-through stream includes pure plasma components (Menon recognizes the term “liquid” to include plasma which would naturally flow through the bottom of the fourth filter after sequential filtration of decreasing pore sizes and “adsorbing nucleic acid from the fluid in a layer of the matrix” ([0068], Abstract))(Pure plasma components would be included in any blood sample), and
wherein the affinity-facilitating material of the fourth filter unit is a silica material capable of absorbing and retaining nucleic acids (DNA and RNA bind to silica matrices with high affinity; Menon, [0088]), and the one or more sample-reservation methods include drying and freezing (This extraction/preservation (thaw/freeze) cycle; Menon, [0097]).
Regarding claim 24, Modified Menon teaches the method of claim 15, further comprising:
separating and retaining a fourth set of blood components from the third passing-through stream (adsorbing nucleic acid from the fluid in a layer of the matrix; Menon, Abstract; See succession of layers 34 to 36 in Fig. 2) through a fourth filter unit (a highly adsorbent RNA/DNA preservation layer 36 (alternatively described as the RNA/DNA adsorption layer); Menon, [0087]), made of an affinity-facilitating material (DNA and RNA bind to silica matrices with high affinity; Menon, [0088]), letting through a remaining passing-through stream (“The bottom of the insert 60…contain..any fluids within the fluid collection portion 46 of the housing 42,” and since the nucleic acid adsorbs to the preservation layer 36 directly above the insert 60, unadsorbed fluid would naturally collect here; Menon, [0087]), wherein the fourth set of blood components includes small protein or nucleic acid components (adsorbing nucleic acid; Abstract),
wherein the fourth filter unit is stacked behind the third filter unit in a direction of the whole blood sample passes through the filter (See the sequential arrangement of filters 34-36 in Fig. 2 of Menon), and is detachably connected to the third filter unit (“each holder 64 is capable of removably engaging at least one adjacent holder 64,” wherein each holder 64 encases a separate filter 32-36; Menon, [0091]; Figs. 2-3) with a predetermined space separating therebetween (A plurality of stacks of filter sheets 28 are positioned within housing 12 separated by annular spacers 27 throughout the height of the housing 12; Proulx, p. 13, ll. 4-6) and disassembled after filtering, wherein after the fourth filter unit is disassembled after filtering the whole blood sample, the fourth set of blood components retained at the fourth filter unit are collected for a fourth further test or experiment pertaining to the fourth set of blood components (See the results of total protein concentration and RNA post-loading in Figs. 9-12 of Menon)(This pie-shaped design of the membrane 32, 34, 36 allows a user to easily separate sections of each of the membrane 32, 34, 36 for easy partial sample analysis, leaving other sections of the membrane available for analysis at a later time or for concurrent analysis; Menon, [0092]), or for a purpose of preservation or transportation via one or more sample-preservation methods, and the remaining passing-through stream includes pure plasma components (Menon recognizes the term “liquid” to include plasma which would naturally flow through the bottom of the fourth filter after sequential filtration of decreasing pore sizes and “adsorbing nucleic acid from the fluid in a layer of the matrix” ([0068], Abstract))(Pure plasma components would be included in any blood sample), and
wherein the affinity-facilitating material of the fourth filter unit is a silica material capable of absorbing and retaining nucleic acids (DNA and RNA bind to silica matrices with high affinity; Menon, [0088]), and the one or more sample-reservation methods include drying and freezing (This extraction/preservation (thaw/freeze) cycle; Menon, [0097]).
Claims 8, 10, 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Menon et al. (US 20140273058 A1), as evidenced by Pall Life Sciences (“Vivid™ Plasma Separation Membrane; 2009), in view of Marble et al. (US 20130184446 A1), Lee et al. (US 20150090674 A1), Burg et al. (US 20140263059 A1) and Proulx et al. (WO 0032290 A1, see attached English translation), as applied to claim 1 and 15 above, and in further view of Hillman et al. (US 5135719 A, 1990), and Fisher Scientific (“A clarifying guide to Membrane Filtration”; 2017).
Regarding claim 8, Modified Menon teaches the filter according to claim 1.
Modified Menon is silent to teaching the first filter unit has a micron rating of 2-5 um, and a hole-up-volume of 20-100 uL.
Hillman teaches a micron rating of 2-5 µm (Particle size retention is preferably from about 1.0 to 3.0 microns; column 3, lines 66-67).
Hillman is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating blood components and explores the use of filters capable of separating red blood cells from plasma starting with a whole blood sample (column 1, lines 59-61) as performed by the first filter described by Marble. 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 filter system taught by Menon in view of Marble, Lee, Burg, and Proulx to incorporate the teachings of Hillman by specifying the first filter to have a micron rating of 2-5 µm. Hillman states “particle size retention, composition of…thickness, and density should be taken into consideration in order to provide adequate filtration without hemolysis” (column 3, lines 59-62) as well as “to allow plasma to pass more rapidly through the filter than the red blood cells” (column 2, lines 2-3). In short, using the ranges of thickness with the corresponding particle size retention described by Hillman will prevent red blood cells from being destroyed and ultimately result in the partial separation of blood components from the whole blood sample. In the case where the claim ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists (MPEP 2144.05(I)). It would have been obvious to try to optimize these result-effective variables due to the finite number of predictable potential solutions so as to achieve the maximum separation without cell damage (See MPEP 2144.05(I) and MPEP 2143(I)(E)).
Modified Menon is silent to teaching a hole-up-volume of 20-100 µL.
Fisher Scientific teaches a hole-up-volume of 20-100 µL (Improving Throughput table shows hold up volume column ranging from 10-80 µL with corresponding values for sample volume and, filter size and filtration area; page 18).
Fisher Scientific is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating blood components and explores the use of filters capable of separating red blood cells from other components (page 4) as performed by the first filter described by Marble. 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 filter system taught by Menon in view of Marble, Lee, Burg, Proulx and Hillman to further incorporate the teachings of Fisher Scientific by specifying the first filter to have a hole-up-volume of 20-100 µL. As shown on page 18 by Fisher Scientific, the hold up volume is a function of the sample volume, filter size, and filtration area. The hold up volume can also depend on other parameters such as the material composition of the filtration, pressure, volume and the other parameters of the claim: weight, thickness, and micron rating. It would have been obvious before the effective filing date of the claimed invention to have tried to optimize the holdup volume range along with the other variables due to the finite number of predictable potential solutions so as to achieve better separation of whole blood cell components with a reasonable expectation of success (See MPEP 2143(I)(E) and MPEP 2144.05(I)).
Regarding claim 10, Modified Menon teaches the filter according to claim 1, wherein the second filter unit has a micron rating of 1-5pm, and a hole-up-volume of 2-10 uL.
Modified Menon is silent to teaching the first filter unit has a micron rating of 2-5 pm, and a hole-up-volume of 20-100 uL.
Modified Menon does teach a hole-up-volume (void volume) of the asymmetric membrane is ~20 ± 1 μL/cm2 (see page 2, column 1, paragraph 2, lines 7-8 of the attached product data sheet for Pall Life sciences).
Hillman teaches a micron rating of 2-5 µm (Particle size retention is preferably from about 1.0 to 3.0 microns; column 3, lines 66-67).
Hillman is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating blood components and explores the use of glass microfiber filters capable of separating red blood cells from plasma starting with a whole blood sample (column 1, lines 59-61) as performed by the first filter described by Marble. 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 filter system taught by Menon in view of Marble, Lee, Burg, and Proulx to incorporate the teachings of Hillman by substituting the second filter unit for a filter unit with a micron rating of 2-5 µm. Hillman states “particle size retention, composition…glass thickness, and density should be taken into consideration in order to provide adequate filtration without hemolysis” (column 3, lines 59-62) as well as “to allow plasma to pass more rapidly through the filter than the red blood cells” (column 2, lines 2-3). In short, using the micron rating range described by Hillman will prevent red blood cells from being destroyed and ultimately the partial separation of blood components from the whole blood sample which is a shared goal of reference Menon. It would have been obvious before the effective filing date of the claimed invention to optimize the well-known variable of micron rating to be 2-5 um so as to obtain the desired predictable result of efficient separation. (See MPEP 2144.05(I)), MPEP 2143(I)B)).
Modified Menon is silent to teaching a hole-up-volume of 2-10 uL.
Fisher Scientific teaches a hole-up-volume of 10-80 µL (Improving Throughput table shows hold up volume column ranging from 10-80 µL with corresponding values for sample volume and, filter size and filtration area; page 18).
Fisher Scientific is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating blood components and explores the use of filters capable of separating red blood cells from other components (page 4) as performed by the second filter described by Menon. 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 filter system taught by Menon in view of Marble, Lee, Burg, Proulx and Hillman to incorporate the teachings of Fisher Scientific by specifying the second filter to have a hole-up-volume of 20-100 µL. As shown on page 18 by Fisher Scientific, the hold up volume is a function of the sample volume, filter size, and filtration area. The hold up volume can also depend on other parameters such as the material composition of the filtration, pressure, volume and the other parameters of the claim: weight, thickness, and micron rating. It would have been obvious before the effective filing date of the claimed invention to have optimized this variable of hole-up-volume to be 2-10 uL so as to obtain the desired result of efficient separation. (See MPEP 2144.05(I)).
Regarding claim 16, Modified Menon teaches the method of claim 15.
Modified Menon is silent to teaching the first filter unit has a micron rating of 2-5 um, and a hole-up-volume of 20-100 uL.
Hillman teaches a micron rating of 2-5 µm (Particle size retention is preferably from about 1.0 to 3.0 microns; column 3, lines 66-67).
Hillman is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating blood components and explores the use of filters capable of separating red blood cells from plasma starting with a whole blood sample (column 1, lines 59-61) as performed by the first filter described by Marble. 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 filter system taught by Menon in view of Marble, Lee, Burg, and Proulx to incorporate the teachings of Hillman by specifying the first filter to have a micron rating of 2-5 µm. Hillman states “particle size retention, composition of…thickness, and density should be taken into consideration in order to provide adequate filtration without hemolysis” (column 3, lines 59-62) as well as “to allow plasma to pass more rapidly through the filter than the red blood cells” (column 2, lines 2-3). In short, using the ranges of thickness with the corresponding particle size retention described by Hillman will prevent red blood cells from being destroyed and ultimately result in the partial separation of blood components from the whole blood sample. In the case where the claim ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists (MPEP 2144.05(I)). It would have been obvious to try to optimize these result-effective variables due to the finite number of predictable potential solutions so as to achieve the maximum separation without cell damage (See MPEP 2144.05(I) and MPEP 2143(I)(E)).
Modified Menon is silent to teaching a hole-up-volume of 20-100 µL.
Fisher Scientific teaches a hole-up-volume of 20-100 µL (Improving Throughput table shows hold up volume column ranging from 10-80 µL with corresponding values for sample volume and, filter size and filtration area; page 18).
Fisher Scientific is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating blood components and explores the use of filters capable of separating red blood cells from other components (page 4) as performed by the first filter described by Marble. 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 filter system taught by Menon in view of Marble, Lee, Burg, Proulx and Hillman to further incorporate the teachings of Fisher Scientific by specifying the first filter to have a hole-up-volume of 20-100 µL. As shown on page 18 by Fisher Scientific, the hold up volume is a function of the sample volume, filter size, and filtration area. The hold up volume can also depend on other parameters such as the material composition of the filtration, pressure, volume and the other parameters of the claim: weight, thickness, and micron rating. It would have been obvious before the effective filing date of the claimed invention to have tried to optimize the holdup volume range along with the other variables due to the finite number of predictable potential solutions so as to achieve better separation of whole blood cell components with a reasonable expectation of success (See MPEP 2143(I)(E) and MPEP 2144.05(I)).
Regarding claim 17, Modified Menon teaches the method of claim 15.
Modified Menon is silent to teaching the first filter unit has a micron rating of 2-5 um, and a hole-up-volume of 20-100 uL.
Modified Menon does teach a hole-up-volume (void volume) of the asymmetric membrane is ~20 ± 1 μL/cm2 (see page 2, column 1, paragraph 2, lines 7-8 of the attached product data sheet for Pall Life sciences).
Hillman teaches a micron rating of 2-5 µm (Particle size retention is preferably from about 1.0 to 3.0 microns; column 3, lines 66-67).
Hillman is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating blood components and explores the use of glass microfiber filters capable of separating red blood cells from plasma starting with a whole blood sample (column 1, lines 59-61) as performed by the first filter described by Marble. 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 filter system taught by Menon in view of Marble, Lee, Burg, and Proulx to incorporate the teachings of Hillman by substituting the second filter unit for a filter unit with a micron rating of 2-5 µm. Hillman states “particle size retention, composition…glass thickness, and density should be taken into consideration in order to provide adequate filtration without hemolysis” (column 3, lines 59-62) as well as “to allow plasma to pass more rapidly through the filter than the red blood cells” (column 2, lines 2-3). In short, using the micron rating range described by Hillman will prevent red blood cells from being destroyed and ultimately the partial separation of blood components from the whole blood sample which is a shared goal of reference Menon. It would have been obvious before the effective filing date of the claimed invention to optimize the well-known variable of micron rating to be 2-5 um so as to obtain the desired predictable result of efficient separation. (See MPEP 2144.05(I)), MPEP 2143(I)B)).
Modified Menon is silent to teaching a hole-up-volume of 2-10 uL.
Fisher Scientific teaches a hole-up-volume of 10-80 µL (Improving Throughput table shows hold up volume column ranging from 10-80 µL with corresponding values for sample volume and, filter size and filtration area; page 18).
Fisher Scientific is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating blood components and explores the use of filters capable of separating red blood cells from other components (page 4) as performed by the second filter described by Menon. 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 filter system taught by Menon in view of Marble, Lee, Burg, Proulx and Hillman to incorporate the teachings of Fisher Scientific by specifying the second filter to have a hole-up-volume of 20-100 µL. As shown on page 18 by Fisher Scientific, the hold up volume is a function of the sample volume, filter size, and filtration area. The hold up volume can also depend on other parameters such as the material composition of the filtration, pressure, volume and the other parameters of the claim: weight, thickness, and micron rating. It would have been obvious before the effective filing date of the claimed invention to have optimized this variable of hole-up-volume to be 2-10 uL so as to obtain the desired result of efficient separation. (See MPEP 2144.05(I)).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Menon et al. (US 20140273058 A1), as evidenced by Pall Life Sciences (“Vivid™ Plasma Separation Membrane; 2009), in view of Marble et al. (US 20130184446 A1), Lee et al. (US 20150090674 A1), Burg et al. (US 20140263059 A1), Proulx et al. (WO 0032290 A1, see attached English translation), Hillman et al. (US 5135719 A, 1990), and Fisher Scientific (“A clarifying guide to Membrane Filtration”; 2017), as applied to claim 8 above, and in further view of Silin et al. (US 20150053627 A1).
Regarding claim 9, Modified Menon teaches the filter according to claim 8, wherein the pore size of the first filter unit is 10 um (the first size-exclusion filter has a pore size of about 10 µm; Marble, [0022]), the thickness range of the first filter unit includes 1000 um (“The filter member may have a thickness in a range from about 0.8 to about 1.2 mm,” wherein this equates to a range of 800-1200um; Lee, [0029]), the micron rating range of the first filter unit includes 3 um (Particle size retention is preferably from about 1.0 to 3.0 microns; Hillman, column 3, lines 66-67), and the hole-up-volume range of the first filter unit includes 50 uL (Improving Throughput table shows hold up volume column ranging from 10-80 µL with corresponding values for sample volume and, filter size and filtration area; Fisher Scientific, page 18).
Selecting the claimed thickness of 1000 um, micron rating of 3 pm, and hole-up-volume of 50 ul is optimization of a routine result-effective variable to yield the predictable outcome of a better separation of blood sample components (See MPEP 2144.05(I)). It would have been obvious before the effective filing date of the claimed invention to have chosen these filter characteristics so as to achieve such a benefit.
Modified Menon is silent to the teaching of the weight being 250 gram/m2.
Silin teaches the weight being 250 gram/m2 (the filter media may have a basis weight…equal to about 250 g/m.sup.2; ([0040]).
Silin is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating blood components by using a multilayer filter ([0024][0085]). 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 filter system taught by Menon in view of Marble, Lee, Burg, Proulx, Hillman, and Fisher Scientific to incorporate the teachings of Silin by specifying the first filter weight to be 250 gram/m2. Doing so will help to achieve “enhanced filtration properties” which is the ultimate goal of Menon for the separation of whole blood components. It would have been obvious before the effective filing date of the claimed invention to have optimized this variable of filter weight to be 250 g/m.sup.2 so as to obtain the desired result of efficient separation. (See MPEP 2144.05(I)).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Menon et al. (US 20140273058 A1), as evidenced by Pall Life Sciences (“Vivid™ Plasma Separation Membrane; 2009), in view of Marble et al. (US 20130184446 A1), Lee et al. (US 20150090674 A1), Burg et al. (US 20140263059 A1), Proulx et al. (WO 0032290 A1, see attached English translation), Hillman et al. (US 5135719 A, 1990), and Fisher Scientific (“A clarifying guide to Membrane Filtration”; 2017), as applied to claim 10 above, and in further view of Streiff (US 20190382699 A1), and Leland et al. (US 20180369473 A1).
Regarding claim 11, Modified Menon teaches the filter according to claim 10.
Modified Menon fails to teach the pore size of the second filter unit is 0.1 µm, the thickness of the second filter unit is 300 um, the weight of the second filter unit is 200 gram/m2, the micron rating of the second filter unit is 2 um, and the hole-up-volume is 5 uL.
Streiff teaches the pore size of a filter unit is 0.1 µm (the size selective filter comprises pores with a diameter..of 0.1 μm; [0011]).
Streiff is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating blood components. 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 filter system taught by Menon in view of Marble, Lee, Burg, Proulx, Hillman, and Fisher Scientific to incorporate the teachings of Streiff by substituting the second filter unit for a filter unit with a pore size of 0.1 μm. Choosing an even smaller pore size (from 0.2 µm 0.1 µm) is still not smaller than the pore size of the third filter that is 0.01 µm. Therefore, adjusting the second filter pore size to 0.1 µm would serve the same purpose by yielding the predictable result of separating cell fragments, a function that is well known in the art (See MPEP 2143(I)(B)).
Modified Menon fails to teach the hole-up-volume is 5 µL.
Leland teaches the hole-up-volume is 5 µL (the dead volume will be about 5 μL; [0076]).
Leland is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating blood components. 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 filter system taught by Menon in view of Marble, Lee, Burg, Proulx, Hillman, Fisher Scientific, and Streiff to incorporate the teachings of Leland by substituting the first filter unit for a filter unit having a hole-up-volume of 5 µL. Leland already teaches “for optimal blood filtration, the pore size is recommended to be less than 2 microns” ([0058]) and further explains that “A low dead volume take-off maximizes the plasma recovery efficiency, which is necessary when the available blood volumes are limited” ([0037]). Adjusting the hole-up-volume to be 5 µL would serve the same purpose by yielding the predictable result of maximizing cell fractionation, a function that is well known in the art (See MPEP 2143(I)(B)).
Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Menon et al. (US 20140273058 A1), in view of Valkirs et al. (US 20040219509 A1), Marble et al. (US 20130184446 A1), and Lee et al. (US 20150090674 A1).
Regarding claim 21, Menon teaches a method of measuring blood (whole blood; [0019]; See measurements in Figs. 7, 9-11) by using a disease diagnosis kit (all equipment in Figure 2) including a multi-layered filter (an integrated membrane assembly 30; [0087]; Fig. 2), the method comprising:
separating and retaining blood platelets including P-selectin, ]) letting through a second passing-
through stream (“The porosity of the membrane was carefully selected in order to trap and remove cell/cellular debris while allowing nucleic acid species and proteins to flow through,” wherein cell is defined to include “platelets,” and since P-selectin is localized to platelets and platelet debris then P-selectin would also be separated; [0100][0069 through a first layer of the second filter unit (The sample collection layer 32 comprises an asymmetric membrane that has varying pore size (large to small) across the flow direction of the sample,” wherein the depth of larger pore size is the first layer; [0087]);
separating and retaining proteins in plasma including sP-selectin from the second passing-
through stream through a second layer of the second filter unit having a smaller pore size than the first layer of the second filter unit, letting through a third passing-through stream (“The porosity of the membrane was carefully selected in order to trap and remove cell/cellular debris while allowing nucleic acid species and proteins to flow through,” wherein cell is defined to include “platelets,” and since sP-selectin is localized to platelets and platelet debris then sP-selectin would also be separated; [0100][0069])(“The sample collection layer 32 comprises an asymmetric membrane that has varying pore size (large to small) across the flow direction of the sample,” wherein the depth of larger pore size is the first layer and the depth of the smaller pore size is the second layer);
separating and retaining small protein (a protein adsorption layer 84 designed to selectively remove proteins from the cell free flow through; [0100]) or nucleic acid components from the third passing through stream through a third filter unit letting through a remaining passing-through stream (“a second layer for protein adsorption,” or “a protein adsorption layer 34”; Abstract; [0087]; Fig. 2) and a fourth filter unit (a highly adsorbent RNA/DNA preservation layer 36 (alternatively described as the RNA/DNA adsorption layer); [0087]),
wherein the second and third filter units are sequentially arranged such that the whole blood sample passes through the second unit and third unit in sequence (sequence the filtering process to first filter cells and then proteins to avoid degradation of the nucleic acids; [0026]; See order of layers 32, 34, and 36 of Figs. 2-3),
wherein the second filter unit and the third filter unit are detachably coupled to each other and the third filter unit and the fourth filter unit are detachably coupled to each other (“each holder 64 is capable of removably engaging at least one adjacent holder 64,” wherein each holder 64 encases a separate filters 32, 34, and 36; [0091]; Figs. 2-3),
wherein the second filter unit, the third filter unit, and the fourth filter unit are disassembled after the separating and retaining of the small protein or the nucleic acid components, and wherein after the second filter unit, the third filter unit, and the fourth filter unit are disassembled, the blood platelets retained at the first layer of the second filter unit are collected for a second further test or experiment pertaining to the blood platelets, the proteins in plasma retained at the second layer of the second filter unit are collected for a third further test or experiment pertaining to the proteins in plasma, and the small protein or nucleic acid components retained at the third filter unit and the fourth filter unit are collected for a fourth further test or experiment pertaining to the small protein or nucleic acid components, or for a purpose of preservation or transportation via one or more sample-preservation methods (See the results of total protein concentration and RNA post-loading in Figs. 9-12)(This pie-shaped design of the membrane 32, 34, 36 allows a user to easily separate sections of each of the membrane 32, 34, 36 for easy partial sample analysis, leaving other sections of the membrane available for analysis at a later time or for concurrent analysis; [0092]), and the remaining passing-through stream include pure plasma components (plasma would naturally flow through the bottom of the fourth filter), and wherein the affinity-facilitating material of the fourth filter unit (36; [0083]; Fig. 1) is a silica material capable of absorbing and retaining nucleic acids (Silica membranes are an alternative membrane for nucleic acid capture due to their strong nucleic acid binding capacity; [0088])(DNA and RNA bind to silica matrices with high affinity; [0088]) and adsorbs nucleic acids and the one or more sample-reservation methods include drying and freezing (This extraction/preservation (thaw/freeze) cycle; [0097]).
Menon fails to teach:
measuring P-selectin, a first filter, having a pore size of 5-15 um, a thickness of 500-1500 um, and a weight of 100-400 gram/m2, separating blood cells from a whole blood sample, the first, third, and fourth filter units are stacked on an acrylic plate (emphasis added), and each of the filter units having different pore sizes,
the blood cells retained at the first filter unit are collected for a first further test or experiment pertaining to the blood cells, and
wherein the second filter unit has a pore size smaller than the pore size of the first filter unit, and the third filter unit has a pore size smaller than the pore size of the second filter unit
Valkirs teaches measuring P-selectin (detecting the level of P-selectin glycoprotein ligand-1 (PSGL-1) expressing T cells in a sample from the subject; Abstract)
Valkirs is considered to be analogous to the claimed invention because it is in the same field of endeavor for separating proteins in a blood sample. 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 modified the filter method taught by Menon to incorporate the teachings of Valkirs by utilizing the multilayer filter to measure P-selectin in a blood sample. Reference Menon teaches that “information derived from the analysis of proteins and nucleic acids derived from blood and other fluids and tissues has provided early detection of and diagnosis capability for many medical conditions,” and the multi-layer filter disclosed in the reference provides a means for gathering this information. Valkirs recognizes that “test samples would be more readily analyzed following a fractionation or purification procedure, for example, separation of whole blood into serum or plasma components” ([0031]) when using P-selectin as biomarker to identify particular diseases ([0016]); however, utilizing the multi-layer filter taught by modified Menon would help to optimize this separation process. It would have been obvious to try utilizing the multilayer filter to measure P-selectin in a blood sample in order to meet the need for a useful disease diagnostic method because there are a finite number of identified predictable potential solutions for isolating P-selectin in a blood sample, and one of ordinary skill in the art would expect a reasonable expectation of success in doing so (MPEP 2143(I)(E)).
Modified Menon fails to teach:
a first filter, having a pore size of 5-15 um, a thickness of 500-1500 um, and a weight of 100-400 gram/m2 separating blood cells from a whole blood sample, the first, third, and fourth filter units are stacked on an acrylic plate (emphasis added), and each of the filter units having different pore sizes, and the blood cells retained at the first filter unit are collected for a first further test or experiment pertaining to the blood cells, and
wherein the second filter unit has a pore size smaller than the pore size of the first filter unit, and the third filter unit has a pore size smaller than the pore size of the second filter unit.
Marble teaches:
a first filter unit, having a pore size of 5-15 um, (the first size-exclusion filter has a pore size of about 10 µm; [0022]), separating blood cells (excludes passage therethrough of lymphocytes, monocytes, neutrophils, eosinophils, and basophils; [0015]) from a whole blood sample (the sample comprises whole blood; [0013]), and
the second filter unit has a pore size smaller than the pore size of the first filter unit, and the third filter unit has a pore size smaller than the pore size of the second filter unit (This limitation is fulfilled by the prior art in that the first filter is 10 µm, the second filter is 0.2 µm (Menon), and the third filter is 0.01 µm (“the shearing filter has a pore size of about 0.01-0.4 µm,” such that “microorganism nucleic acid is released”;[0022],[0015]. See overlapping ranges statement below).
Marble is considered to be analogous to the claimed invention because it is in the same field of endeavor for a multi-layered filter for separating blood components. Primary reference, Menon, teaches the third layer (protein adsorption layer) allows nucleic acids RNA/DNA to pass through ([0083]), while Marble uses a shearing filter to release nucleic acids using a pore size of 0.01-0.4 µm ([0015]). Menon teaches the second layer (sample collection layer) to be an 0.2 µm asymmetric membrane comprising larger pores on an upstream portion and smaller pores on a downstream portion, where the larger upstream pores act as a pre-filter while the smaller downstream pores serve as an absolute cut-off layer, enabling the efficient captures of cells while reducing clogging ([0085]). 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 multi-layered filter taught by Menon in view of Valkirs to incorporate the teachings of Marble by adding a first filter unit above the second filter unit, having a pore size of 5-15 um, separating blood cells from a whole blood sample, and adding 0.01 µm pores to the third filter, because this would reduce clogging in the subsequent layers by removing bulk whole blood cells early and provide an additional size exclusion separation technique to recover nucleic acids, and this involves combining prior art elements according to known methods to yield predictable results (See MPEP 2143(I)(A)).
Modified Menon fails to teach the third filter unit has a pore size of 0.003-0.01 um (emphasis added). Modified Menon instead teaches that the third filter has a pore size of about 0.01 μm which is a partial overlap (Marble, [0015]) of the claimed range. Primary reference, Menon, teaches a protein-removal layer in a stacked filter assembly (See Fig. 2) and explicitly states that each layer is a porous membrane ([0088]) used to deplete proteins so nucleic acids are preserved for downstream analysis (Abstract). One of ordinary skill in the art seeking to ensure protein separation (the function of the third filter as stated in the abstract of the instant publication US20220168672A1) would naturally look to known pore-size implementations for fine cutoffs. Marble discloses a downstream filter stage with pores as small as about 0.01 um within the same kind of multi-stage, blood sample filtration stack as Menon, demonstrating the feasibility and predictability of using micro to sub-micron cutoffs in this context. Pore size is a result-effective variable governing what passes or what is retained. Because Marble touches the claimed band at 0.01 um, modifying the filter taught by Menon by selecting a 0.01 um filter, and then routinely optimizing this result-effective variable to slightly below (0.003-0.01) would have been obvious to one having an ordinary skill in the art before the effective filing date of the invention (MPEP 2144.05(I)).
Modified Menon fails to teach:
a first filter, having a thickness of 500-1500 um, and a weight of 100-400 gram/m2.
Lee teaches a filter having a thickness of 500-1500 um (“The filter member may have a thickness in a range from about 0.8 to about 1.2 mm,” wherein this equates to a range of 800-1200um; [0029]), and a weight of 100-400 gram/m2 (The filter member may have a weight per surface area (or a basis weight) in a range from about…70 to about 120 g/m.sup.2; [0029]).
Lee is considered to be analogous to the claimed invention because it is in the same field of endeavor for a multi-layered filter for separating blood components. 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 multi-layered filter taught by Menon in view of Valkirs and Marble to incorporate the teachings of Lee by adding a first filter, having a thickness of 500-1500 um and a weight of 100-400 gram/m2, in order to “to reduce the occurrence of hemolysis of corpuscles including erythrocytes” (Lee, [0028]). Primary reference, Menon expresses a desire to collect blood cells without lysis ([0101]). Secondary reference Marble teaches staged size-exclusion filters with the first filter dimensioned for whole-cell capture ([0015]). Lee teaches that blood filter members having a thickness and weight per surface area in a particular range provide high plasma recovery while preventing hemolysis ([0028][0029]). It would have been advantageous to select Lee’s disclosed thickness and weight to modify the first filter of Menon in view of Valkirs and Marble to ensure durability, capacity, and reduced cell lysis, as both Lee and Menon stress the importance of avoiding red blood cell rupture. The overlapping filter weight range between the teaching of Lee and the instant claim is a matter of optimizing a routine result-effective variable to yield the predictable outcome of a lower amount of lysed cells (See MPEP 2144.05(I)). It would have been obvious before the effective filing date of the claimed invention to have chosen these filter characteristics so as to achieve such a benefit.
Regarding claim 22, Modified Menon teaches the method of claim 21, wherein the whole blood sample is collected from stroke patients, and sP-selectin is found in the small protein (“Blood samples from patients with stroke,” wherein “P-selectin [is] also called granule membrane protein-140,” wherein paragraph [0075] of the instant publication US 20220168672 A1 states that “but when exposed to diseases such as stroke, it is converted to sP-selectin”; Valkirs, [0276];[0137]), separated, retained, and collected via the fourth further test or experiment (“The nucleic acid species remaining in the sample flow through were stabilized and preserved in the RNA/DNA adsorption layer 86,” which would thereby separate any extra blood components including small proteins from the nucleic acids; Menon, [0100]).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALERIE SIMMONS whose telephone number is (703)756-1361. The examiner can normally be reached M-F 7:30-4:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maris Kessel can be reached on 571-270-7698. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/V.S./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758
Prosecution Insights