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 .
DETAILED ACTION
Claims 1, 4, 6-7 and 9-10 are pending.
Claims 9 and 10 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected Group II. Election was made without traverse in the reply filed on 16 July 2025 to the Restriction/Election Office Action mailed 20 June 2025.
Claims 1, 4 and 6-7 are rejected.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. §119(e) or under 35 U.S.C. §120, §121, or §365(c) is acknowledged. As noted in the Non-Final Office Action mailed 08 September 2025, this application is a 371 of PCT/CN2021/075263, filed 02/04/2021. Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. §119 (a)-(d).
Claims 1, 4 and 6-7 have the effective filing date of 27 October 2020.
Claim Rejections - 35 U.S.C. § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. §102 and §103 (or as subject to pre-AIA 35 U.S.C. §102 and §103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. §103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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, 4 and 7 are rejected under 35 U.S.C. §103 as being unpatentable over Zou et al. (Pub. No. CN103149370A; Pub. Date: 2013-06-12; see English machine translation (Eng MT) as NPL for page/para. numbers) in view of Terpstra et al. (Anal. Biochem. 1981, 111: 149-157).
Claim 1 recites the terms: "NaCl", "EDTA", "KBr" and "NaBr". In the chemical arts, NaCl stands for sodium chloride; EDTA stands for ethylenediaminetetraacetic acid; KBr stands for potassium bromide; and NaBr stands for sodium bromide.
Regarding claims 1, 4 and 7, Zou et al. teaches Reagent R1 comprising polyethylene glycol-6000 (pg. 1, Abstract [ethylene glycol, per claim 1]). The concentration of polyethylene glycol-6000 is 5- 25g/L (pg. 1, Abstract [25g/L = 2.5%], a buffer system, which is HEPES (pg. 1, Abstract), sodium chloride NaCl and EDTA (pg. 1, Abstract) The concentration of HEPES is 0.5-10g/L (pg. 1, Abstract [10g/L/238.3g/mole = 42.0mM]). The pH value of the HEPES is 5.5-8.5 (pg. 5, para. 4).
Zou et al. does not specifically teach: (1) an alcohol substance selected from a group which includes ethylene glycol; (2) the diluent is one of a KBr solution, a NaBr solution or a sucrose solution [Claim 1]; 3) the buffer solution has a concentration of 20mM [Claim 1]; and 4) a diluent, a density liquid and a buffer solution in a volumetric ratio of 1: (35-45): (110-130), respectively [Claim 1].
Terpstra et al. teaches serum stored at 4oC before ultracentrifugation (pg. 150, column 2, lines 7-8). Pre-stained serum was overlayed with a salt solution (NaCl and KBr). All solutions contained ethylenediaminetetraacetic acid (EDTA) disodium salt (pg. 150, column 2, para. 1 [nexus to Zou et al.- density liquid consisting of NaCl and EDTA]). In some tests, ethylene glycol was added to unstained sera before ultracentrifugation (pg. 153, column 1, para. 1; and pg. 154, Table 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the reagent for detecting lipoprotein particle concentration comprising a density liquid containing NaCl and EDTA and a buffer solution, as taught by Zou et al., by adding an alcohol substance such as ethylene glycol to the density buffer at a specific concentration. Optimizing a density liquid (used in a centrifugation technique) by replacing the PEG-6000, taught by Zou et al., with ethylene glycol, taught by Terpstra et al. would have the reasonably predictable results that the ethylene glycol would have successfully detected or isolated lipoprotein (MPEP 2143 (I)((B)(3)(E)(G) and MPEP 2144.05 (II)(III)) because Terpstra et al. teaches adding ethylene glycol to an ultracentrifugation procedure for separating lipoprotein fractions, and Zou et al. teaches centrifuging samples containing lipoprotein after Reagent R2 was added in order to quantify apolipoprotein (Zou et al., pg. 9, para. 4 thru pg. 10, cont. para. 4).
It would have been further obvious to have separated the various chemical reagents (i.e., ethylene glycol, NaCl, EDTA, HEPES buffer and KBr and/or sucrose, as shown by the cited prior art) into three distinct reagent solutions, such as a diluent, a density liquid and a buffer solution, and combined them in a specific volumetric ratio [Claim 1], so as to allow the end user to optimize the concentrations of each chemical compound in order to produce a desired volumetric ratio for a specific use (MPEP 2144.05 (II)(III)).
Terpstra et al. teaches that several different classes of lipoprotein (VLDL (very low density lipoprotein), LDL (low density lipoprotein), HDL (high density lipoprotein) etc.) can be separated in one density gradient centrifugation step (pg. 149, column 1, para. 1; and Abstract). Figure 3 also shows the additional separation of IDL (intermediate density lipoprotein) from HDL, VLDL and LDL (Terpstra et al., pg. 151, Fig. 3). That is, in order to produce distinct bands of one or more lipoproteins in one ultracentrifugation tube, the density would have to be optimized. Therefore, one of ordinary skill in the art of density gradient centrifugation would have been able to have optimized the specific gravity of the resulting centrifugation medium by accessing the desired chemical compounds as separate components combined into an optimized volumetric ratio.
It would have been obvious to one of ordinary skill in the art of preparing a reagent (particularly for its use in a commercially-available kit) to have aliquoted the various chemical compounds into separate solutions (e.g., into separate containers), as a so-called 'diluent', 'density liquid', and 'buffer solution', so as to optimize the task of preparing a centrifugation solution at a specific density for a specific purpose (e.g., detecting in a sample one or two or three or four lipoproteins), by facilitating the preparation of a desired volumetric ratio (MPEP 2144 (I)).
One of ordinary skill in the art would have been motivated to have made those modifications, because Zou et al. shows that the described lipoprotein (a) detection kit has the advantages of high detection sensitivity, high accuracy, favorable precision, favorable linearity within detection range, high stability, low production cost and low blank absorbance, and has anti-interference performance (Zou et al., pg. 2, lines 7-10).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 6 is rejected under 35 U.S.C. §103 as being unpatentable over Zou et al. in view of Terpstra et al., as applied to claims 1, 4 and 7 above, and further in view of and Fujii et al. (Pub. No. JPH09285298A; Pub. Date: 1997-11-04; see English machine translation (Eng MT) as NPL for page/para. numbers).
Zou et al. in view of Terpstra et al. do not show that the concentration of the diluent is 1.21g/cm3.
Fujii et al. teaches that EDTA sodium salt and sucrose were added in specific amounts to a serum pool. In addition, sodium chloride and potassium bromide were also added in specific amounts so at to render a specific gravity of 1.21 (pg. 16, lines 5-12 [nexus to Zou et al.- NaCl and EDTA in the density liquid; and nexus to Terpstra et al.- KBr diluent solution] [specific gravity = relative density]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have modified the reagent for detecting lipoprotein particle concentration comprising a density liquid containing NaCl and EDTA and a buffer solution, as taught by Zou et al. in view of Terpstra et al., by formulating the reagent to comprise the diluent in a concentration of 1.21g/cm3, as taught by Fujii et al., with a reasonable expectation of success, because Fujii et al. shows a reagent for measuring HDL comprising a diluent. One of ordinary skill in the art would have been motivated to make this modification because Fujii et al. teaches that the described invention which incorporates the described reagent(s) provides a fast and convenient method for measuring HDL-cholesterol compared to other prior art methods (pg. 6, para. [0008]).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Arguments
Applicant’s arguments, pp. 6-9, filed on 02 December 2025, with respect to the prior art references cited in the 35 U.S.C. §103 rejection, have been fully considered but they are either not persuasive or are moot because the arguments do not apply to the references as they are applied in the context of the current rejection, or as new grounds necessitated by Applicant’s amendment, in which claim 1 was amended.
It is noted that a reference has been added for evidentiary purposes (see MPEP 2144.03(D)).
1. Applicant remarks (pg. 6, para. 6 thru pg. 7, para. 1-2) that the primary reference of Zou does not teach or suggest the feature "the reagent is consisted of the following components: a diluent, a density liquid and a buffer solution, the density liquid is consisted of an alcohol substance with a concentration of 0.1% to 50%, as described in amended claim 1. Terpstra explicitly taught ethylene glycol is used as the stain solvent of Sudan black. Therefore, Terpstra fails to teach or suggest the above feature as recited in amended independent claim 1 of the present disclosure.
However, in response to Applicant, although claim 1 has been amended to describe a reagent that consists of the recited components, these components are known in the prior art in a reagent. It is noted that Applicant has deleted the intended use of the reagent. Even so, the claimed subject matter describes a product which is a combination of chemical compounds which are known in the chemical arts to be used for specific purposes in a laboratory protocol, whether as a single reagent or a combination of different solutions described as the "reagent". That is, the purpose for the use of any of the recited chemical compounds (e.g., the ethylene glycol shown by Terpstra et al.) is not a persuasive argument, since the claimed subject matter merely describes a combination of chemical compounds. Therefore, it would have been obvious to one of ordinary skill in the art of preparing a reagent for use in a specific laboratory protocol to have combined any of the chemical compounds cited in instant claim 1 with a reasonable expectation that a specific solution or solutions could have been prepared.
2. Applicant remarks (pg. 7, para. 3 thru pg. 8, para. 1) that, although PEG (polyethylene glycol) and EG (ethylene glycol) are similar in name, they are two entirely different chemical substances with vastly different chemical properties, mechanisms of action, and biosafety. Replacing PEG with EG may result in irreversible consequences such as reaction failure or distorted test results. One of ordinary skill in the art know that Sudan black cannot dissolve in polyethylene glycol-6000. Since PEG reduces the solubility of relevant substances, theoretically, replacing the alcoholic substance in the density solution with PEG would cause direct aggregation and precipitation of lipoproteins during the reaction, preventing stratification.
However, in response to Applicant, the claimed subject matter describes a reagent and the purported function of the PEG in a solution containing lipoproteins or Sudan black dye is a moot argument. In addition, Applicant's comparison between EG and PEG with regard to their functional properties in a specific laboratory context appears to be so-called opinion, not probative evidence. It is well known that in assessing the probative value of an [expert] opinion, the examiner must consider the nature of the matter sought to be established, the strength of any opposing evidence, the interest of the expert in the outcome of the case, and the presence, or absence of factual support for the expert's opinion (MPEP 716.01 (c)(llI)).
3. Applicant remarks (pg. 8, para. 2 thru pg. 9) that Fujii fails to teach or suggest the density feature as recited in amended independent claim 1 of the present disclosure. Based on the description of the density solution prepared in Fujii, (i.e., a density solution with a specific gravity of 1.21 was prepared by dissolving 20 g of sucrose, 15 g of potassium bromide, and 5 g of sodium chloride in 100 ml of purified water) it's more impossible for Fujii to provide information that would have motivated one of ordinary skill in the art to have considered modifying the reagent for detecting lipoprotein particle concentration comprising a density liquid containing NaCl and EDTA and a buffer solution, as shown by Zou et al. by adding an alcohol substance to the density buffer at a specific concentration.
However, in response to Applicant, Fujii et al. addresses the limitations of claim 6, but also shows the KBr solution as shown by Terpstra et al. within the context of the density cited in claim 6. Therefore, it would have been obvious to have adjusted the concentration of the KBr diluent to a density of 1.21g/cm3 or any density desired by the enduser of the reagent.
Further in response to Applicant, the instantly-claimed subject matter describes a reagent consisting of cited components, which would have been obvious to have combined into a single reagent or series of solutions comprising "a reagent", barring showing of criticality for the specific combination. For example, Lehtonen et al. (Pub. No. WO 2016/125027 A1 (provided here)) shows an automated solution dispenser that can accurately dose, mix, degas, filter and bottle solutions with minimal human intervention (pg. 1, para. [0003]). In some embodiments, the at least one target characteristic of a prepared solution may be selected from a group which includes, minimally, pH, chemical composition, and density (pg. 2, para. [0004]). The laboratory solution is selected from the solutions listed in Groups 1-36 (pg. 18, para. [0062]). Group 35 comprises, minimally, sodium bromide, 30% v/v methanol, 30%v/v ethanol, 40%v/v tert-butanol, EDTA (ethylenediaminetetraacetic acid), and sucrose (pg. 150, para. [00372] thru pg. 151, cont. para. [00372] [per instant claim 1]); and Group 2 comprises, minimally, sodium chloride, potassium bromide, and HEPES buffer, pH7.0 (pg. 97; and pg. 99, cont. para. [00339] [per instant claims 1 and 7]). That is, the apparatus shown by Lehtonen et al. could have been used to have prepared the reagent as described in instant claim 1.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHARON M PAPCIAK whose telephone number is (571)272-6235. The examiner can normally be reached M-F 8:30am-5:00pm.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/SMP/Examiner, Art Unit 1657