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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Withdrawn Objections/Rejections
The objections to the specification are withdrawn in response to the amendments.
The objections to claims 3 and 6 are withdrawn in response to the amendments.
The rejections of the claims under 112a written description, are withdrawn in response to the amendments.
The rejections of the claims under 103 are withdrawn in response to the amendments. However, new grounds of rejection are set forth below.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/EP2021/051577, filed 01/25/2021. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. DE10 2020 102 038.4, filed on 01/28/2020 in Germany.
Status of the Claims
Claims 1-2, 4-5 and 8-11 are pending; claims 1 and 11 are amended, claims 3 and 6-7 are canceled; claims 8-10 are withdrawn. Claims 1-2, 4-5 and 11 are examined below.
Maintained Objection
Claim Objections
Claim 11 is objected to because of the following informalities:
Claim 11 recites “Diagnostic reagent for quantitative determination of procalcitonin in a sample…”. However, the claim should recite “A diagnostic reagent for quantitative determination of procalcitonin in a sample…” (annotations added) to conform with conventional claim language.
Appropriate correction is required.
New Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Zeng (CN 109959797 A) (Cite No. C of IDS 7/26/2022) in view of Luotola et al. (US 6,358,753 Bl)-Cite No. 1 of IDS 8/16/2024 as evidenced by JSR, IMMUTEX (retrieved online https://www.jsrlifesciences.com/en/research-reagents-ivd/immutex on 9/30/2025) and Nagasaki et al. (WO 2010082681) (Cite No. FP2 of IDS 5/27/2025) (“Nagasaki”).
Regarding claims 1 and 11, Zeng suggests a diagnostic reagent for quantitative determination of procalcitonin in a sample (“[p]rocalcitonin… level in plasma increases in severe bacterial, fungal, and parasitic infections, as well as in sepsis and multiple organ failure. It is an important parameter for diagnosing and monitoring bacterial inflammatory disease infections and therefore has important clinical diagnostic and differential diagnostic value” paragraph 4, “procalcitonin detection kit… comprises R2 reagent…The kit can be applied to detection of the procalcitonin content in the human serum…the highest detection range can reach 100 ng/mL” Abstract, “The kit of the present invention will be described in detail below with reference to specific examples…Example 3 A kind of procalcitonin detection kit is characterized in that, comprises…R2 reagent” paragraphs 35 and 53-54), wherein the reagent is an aqueous suspension of polymer particles with antibodies against procalcitonin covalently bound to said polymer particles (“The R2 reagent includes the following components: 2 to 5g/L of phosphate buffer solutions; 630 to 660mg/L of anti-human procalcitonin antibody polystyrene latex microspheres” Abstract “Latex microsphere suspension” paragraph 59, “latex particles covalently bound to the antibody” paragraph 20) characterised in that - the suspended polymer particles have an average particle size in the range from >300nm to 450 nm (“[t]he particle size of the polystyrene latex microspheres is 330 nm” paragraph 59), - the suspension comprises a proportion of sugar or sugar alcohol dissolved therein in the range from 25 to 250 g/l (“The R2 reagent includes the following components…trehalose 37 g/L” paragraph 57), and - the suspension has a pH in the range from 8.5 to 10 (“the phosphate buffer in the R2 reagent The pH of the liquid is from 7.5 to 8.5” paragraph 29). Zeng further teaches that procalcitonin “is an important parameter for diagnosing and monitoring bacterial inflammatory disease infections and therefore has important clinical diagnostic and differential diagnostic value” (paragraph 4). Zeng further teaches that “the present invention provides a procalcitonin detection kit, which aims to solve the technical problems of existing procalcitonin detection methods, such as low detection efficiency, high cost, unstable test results, low accuracy, and poor repeatability” (paragraph 4). Zeng fails to teach all the limitations of claim 1 in a manner consistent with anticipation, i.e. the limitations of claim 1 are not in a single embodiment. Zeng teaches a size of 330 nm of the particles in Example 3 and the rest of the limitations in the Abstract, Summary and Detail embodiments. 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 combined the teachings of Zeng from the Abstract, Summary and Detailed Embodiments, with the particle size of 330 nm taught in Example 3 because Zeng teaches that the detection kit taught solves technical problems of existing procalcitonin detection methods, such as low detection efficiency, high cost, unstable test results, low accuracy, and poor repeatability. A person having ordinary skill in the art would have had a reasonable expectation of success because Zeng teaches that Example 3 is a further description of the invention.
Zeng fails to teach wherein the antibodies against procalcitonin covalently bound to the polymer particles are polyclonal antibodies, wherein the suspension has a pH in the range from 9.0 to 10.0, the covalent bond of the antibodies is formed via functional groups disposed on the surface of the polymer particles, wherein the functional groups are chloromethyl groups (-CH2Cl), and wherein the diagnostic reagent is obtained using the method according to claim 8.
Luotola teaches “a method for binding antibody or antigen molecules to solid phase. The reactive compound comprising an antibody or antigen molecule and a solide phase are formed by coupling a specific antibody or antigen molecule to a solid phase using a two-step reaction. The coupling is covalent, between the active groups of the solid phase and the antibody, a fragment thereof or the antigen molecule, in the presence of an anionic surfactant, after adding an alkaline/solution to raise the pH to the basic region” (Abstract). Luotola further teaches that “[t]he bound antibody may be…polyclonal” (col. 1 lines 12-13). Luotola further teaches that the solid phase is “a copolymeric styrenvinylbenzylchloride (S/VBC) particle” (col. 2 lines 5-9). Luotola further teaches that “ Coupling takes place…, whereby the methyl chloride groups react with primary or secondary amino groups of the antibody molecules” (col. 2 lines 47-53). Luotola further teaches that the “Covalent binding is a fairly slow event, and enhancement thereof requires basic pH (8 to 11, preferably pH 9.0)” (col. 2 lines 55-56). Luotola further teaches wherein the diagnostic reagent is obtained using the method according to claim 8, i.e. a method for preparing the diagnostic reagent according to claim 1, comprising covalent binding the antibodies via the functional groups on the surface of the polymer particles at a pH of 3 to 6 (“In the coupling procedure the S/VBC particles are transferred by dialysis to a dilute acid or a buffer solution, preferably to 5 mM HCl (pH 2 to 6” col. 2 lines 62-64).
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 teachings of Zeng to rely on the antibodies against procalcitonin being polyclonal antibodies, and the covalent bond of the antibodies being formed via chloromethyl groups (-CH2Cl) taught by Luotola because Luotola suggests this enables a reliable and effective binding of the antibodies to the particles and Zeng is concerned with particles with bound antibodies. It would have been further obvious to have modified the teachings of Zeng to rely on the covalent binding being at a pH of 3 to 6 and the suspension being at a pH from 9.0-10.0 as taught by Luotola because Luotola suggests that this accelerates the time required for covalent coupling of antibodies to the polymer particles, which is a need in the field. A person having ordinary skill in the art would have had a reasonable expectation of success because both Zeng and Luotola are drawn to polymer particles with covalently bound antibodies.
Regarding claim 2, Zeng in view of Luotola teach wherein the polymer of the polymer particles is polystyrene (Abstract of Zeng).
Claims 4 is rejected under 35 U.S.C. 103 as being unpatentable over Zeng in view of Luotola as applied to claim 1 above, and further in view of Althaus et al. (US 20030181662 A1) (Cite No. 1 of IDS 2/7/2023) (“Althaus”).
Regarding claims 4, Zeng in view of Luotola teach the diagnostic reagent according to claim 1 as discussed above.
Zeng further teaches that the highest procalcitonin concentration that can be detected is 100 ng/mL (“the highest [t]he detection range can reach 100ng/mL” paragraph 20).
Zeng in view of Luotola fail to teach wherein the sugar or sugar alcohol is selected from sucrose, mannitol, sorbitol, xylitol, maltitol, raffinose, rhamnose, and combinations thereof.
Althaus teaches anti-procalcitonin antibodies as diagnostic agents or as an ingredient of a diagnostic agent for quantitative determination of procalcitonin in a sample (“diagnostic agents” Abstract, “the antibodies according to the invention as a diagnostic agent, [or] as an ingredient of a diagnostic agent” paragraph 46, “[i]n case of a "in vitro diagnostic agent" the analyte to be detected, for example procalcitonin…, is detected in a sample outside a living human or animal organism and/or the concentration or amount thereof is determined” paragraph 47, “[t]he invention may also be used in particular in a process for the quantitative or qualitative detection of an analyte, preferably procalcitonin” paragraph 50). Althaus further suggests the anti-procalcitonin antibodies are bound to polymer particles in an aqueous suspension, wherein the polymer particles have an average size >300 to 450 nm (“the antibodies according to the invention may also be associated to a solid phase” paragraph 64, “Microparticles are commonly used as solid phase…having an approximate diameter…very particularly preferably between 0.15 and 2 µm…Preferred microparticles are particles suspendable in aqueous solutions and comprising water-insoluble polymer material…Very particularly preferred are latex particles made of, for example, polystyrene” paragraph 75). Althaus further suggests the suspension comprising 40g/l sucrose dissolved therein (“Detection of pCT in a … the abovementioned polymer was mixed with 200 µl of antibody solution… resuspended in 4 ml of imidazole buffer … (5 g/l imidazole, 40 g/l sucrose” paragraphs 177-181). Althaus further teaches “Table 4 Standard curve and measurement of samples…ng pCT/ml…250…125…2 [ng/mL]” page 13).
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 teachings of Zeng in view of Luotola to rely on the sugar being sucrose taught by Althaus because it would have been a simple matter of applying a known technique to a known method. In this case, both Zeng in view of Luotola and Althaus teach anti-procalcitonin antibodies bound to polymer particles in an aqueous suspension, wherein the polymer particles have an average size >300 to 450 nm and the suspension comprises a proportion of sugar dissolved therein in the range of 25 to 250 g/l. Althaus simply applies the art-recognized technique of the sugar being sucrose. Therefore, a person having ordinary skill in the art would have found it obvious to apply the art-recognized technique of Althaus to the based method taught by both Zeng in view of Luotola and Althaus. A person having ordinary skill in the art would have had a reasonable expectation of success because both Zeng and Althaus teach a diagnostic reagent for quantitative determination of procalcitonin in a sample, wherein the reagent is an aqueous suspension of latex polystyrene particles with antibodies against procalcitonin covalently bound to said polymer- the suspended polymer particles having an average particle size in the range from >300nm to 450 nm and the suspension comprises a proportion of sugar or sugar alcohol dissolved therein in the range from 25 to 250 g/l.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Zeng in view of Luotola as applied to claim 1 above, and further in view of Tugirimana et al. Clin Chem Lab Med 2009;47(11):1417–1422 DOI 10.1515/CCLM.2009.312 (“Tugirimana”) as evidenced by Zeng’s Table 5 Google Machine Translation (retrieved online https://translate.google.com/?sl=auto&tl=en&op=images 10/2/2025).
Regarding claim 5, Zeng in view of Luotola teach the diagnostic reagent of claim 1 as discussed above.
Zeng further teaches that the absorbance of the suspension at 510nm within 12 months from the time of preparation of the suspension deviates by less than 5% from the initial value on day 0 (“wavelength 510 nm” paragraph 78, “The stability test of the kit reagents obtained in Example 1-3… the data was recorded continuously for 18 months” paragraph 105, “Table 5 The stability of the validity period of the kit reagents obtained in Example 1-3” paragraph 106). Note that Table 5 of Zeng is not included in the foreign patent translation document provided by Applicant. Therefore, a machine translation of Table 5 is being provided and cited on PTO-892. As evidenced by Zeng’s Table 5, the “Example 3”, “Specimen 2” had a measured procalcitonin concentration of 17.58 ng/mL on day 0 (“0 month”), and at “12 months” the concentration measured was 16.71 ng/mL (see page 2). Therefore, this change in measured concentration corresponds to 17.58 – 16.71 = 0.87 / 17.58 = 0.0495 = 4.95%. Note also that at 180 days (“6 months”) the change in concentration was less than 2% (17.58 – 17.31 = 0.27 / 17.58 = 0.0154 = 1.54%). Although Zeng teaches change in concentration, and not change in absorbance, the change in concentration would inherently also correspond to a change in absorbance given that Zeng teaches that “[t]he PCT content in the sample could be calculated on the standard curve according to its absorbance value” (paragraph 86). Note also that Zeng suggests that the method of detection is based on turbidimetry (“That is, by using latex particles covalently bound to the antibody to enhance the immunoprecipitation reaction, agglutination is generated, resulting in increased turbidity, thereby greatly improving the detection efficiency” paragraph 20).
Zeng in view of Luotola fail to teach the absorbance of the suspension at 660 nm.
Tugirimana teaches “[a] new turbidimetric method for assaying serum C-reactive protein based on phosphocholine interaction” (Title). Tugirimana further teaches a “[f]unctional CRP assay… 10 mL of serum was diluted in 960 mL of Tris-calcium chloride buffer… Next, 20 mL of Intralipid®…20% was added. Following preincubation for 30 min in a small laboratory oven at 37C, samples were thoroughly shaken. The L-index of the mixture was measured turbidimetrically with a bichromatic technique at 660 and 700 nm with a Cobas 6000 analyzer” (page 1418 col. 1 para. 4). Tugirimana further suggests that measuring absorbance at 660 nm for turbidimetry facilitates the suppression of optical interference (“In addition, the wavelengths (700/660 nm) chosen for the turbidimetric reading strongly limits optical interference by hemolysis and icterus” page 1420 col. 1para. 3).
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 teachings of Zeng in view of Luotola to rely on the measuring of the absorbance at 660 nm taught by Tugirimana because Tugirimana suggests that this facilitates the limiting of optical interference from hemolysis and icterus. A person having ordinary skill in the art would have had a reasonable expectation of success because both Zeng in view of Luotola and Tugirimana teach turbidimetry in biological samples. Furthermore, Tugirimana teaches the instrument used for the measurements.
Response to Arguments
Applicant's arguments filed 1/12/2026 have been fully considered but they are not persuasive.
Regarding the claim objections, Applicant remarks that “Applicant amends claim 11 in accordance with the suggestion presented on page 4 of the office action” (page 6 para. 5). However, the amendments to claim 11 fail to address that the claim should recite “A diagnostic reagent…” (annotations added) to conform with conventional claim language.
Regarding the 103 rejections,
Applicant argues that “Zeng discloses …the size of the polystyrene particles is in the range of from 220 to 300 nm (cf claim 9 and paragraph. [0013]). Consequently, the present invention distinguishes from said prior art in that the particles of the present invention have an average particle size in the range from > 300 nm to 450 nm, that is significantly larger than the prior art particles” (page 8 para. 2).
However, although Zeng discloses particles in the range from 220 to 300, the Example cited above of Zeng discloses particles in the range of > 300 nm to 450 nm, as claimed (see rejection above for the obviousness analysis).
Applicant further argues that “Additionally, claim 1 has been amended to specify that the suspension has a pH in the range from 9.0 to 10.0. Zeng discloses an upper limit of the pH of the suspension being 8.5 (cf paragraph [0029])” (page 8 para. 3).
However, Luotola is relied upon for the teaching of the pH in the range from 9-10 (see rejection above).
Applicant further argues that “As ZENG discloses a preferred pH of 8.0, this is clearly teaching away from the far higher pH range recited in claim 1” (page 8 para. 3).
However, the teaching of Zeng regarding that pH 8 is the preferred pH is not teaching away from a pH of 9-10.
Applicant further argues that “Zeng fails to disclose or render obvious wherein "the covalent bond of the antibodies is formed via functional groups disposed on the surface of the polymer particles, wherein the functional groups are chloromethyl groups (-CH2Cl)” (page 9 para. 3).
However, Luotola is relied upon for the teaching of the chloromethyl groups (see rejection above).
Applicant further argues that “None of Althaus, Tugirimana, or Shosaku cure the deficiencies of Zeng” (page 11 para. 2).
However, new grounds of rejection are set forth above over Zeng in view of Luotola (see rejections above).
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677