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 .
Election/Restrictions
Applicant’s election of claims 1-11,16-21 in the reply filed on 10/15/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-21 are pending.
Claims 12-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/15/2025.
Claims 1-11, 16-21 have been considered on the merits herein.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Specification
As stated in the Restriction Requirement mailed 9/19/2025, applicants Specification must include (b) CROSS- REFERENCE TO RELATED APPLICATIONS. Currently applicants' specification does not include related applications, i.e. The present application is the national stage entry of International Patent Application No. PCT/EP2021/073003 having a filing date of August 19, 2021, which claims priority to European Patent Application No. 2019166.5 having a filing date of August 19, 2020, as listed in applicants Application Data Sheet filed on 2/14/2023.
Claim Objections
Claims 2-9, 18-21 are objected to because of the following informalities: Each of the claims are missing a comma after “The method according to claim 1”, for example. Each dependent claim should contain a comma after the claim number from which it depends. For example, for claim 2, it should read “The method according to claim 1, …” Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5, 10, 16, 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 5 and 10, the phrase "like" renders the claim(s) indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 16 recites the limitation "the sample processing and measurement" in claim 10. There is insufficient antecedent basis for this limitation in the claim.
Claim 17 recites the limitation "the blood sample" in claim 10. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-11, 18-21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schwager et al. (J. Allergy Clin Immun., 2017, p. 1331-1338.e8, IDS).
Schwager teaches a flow cytometry-based basophil activation test (BAT) comprising obtaining a blood sample, treating the sample with a test substance, i.e. a peanut allergen, specifically peanut oleosins Ara h 14/15, adding a mixture of antibodies each labelled with a different fluorochrome, i.e., PE/Cy7 FcɛRIα, PECD203c, and APC CD63 and measuring the labelled sample using flow cytometry to determine basophil activation based upon antibody labelling. The CD63 positive percentage of CD203c positive cells were calculated (p. 1332, Basophil Activation test). The flow cytometric gating strategy for BAT is shown in Fig. E1 p. 1338.e2, which shows forward scatter (FSC) area vs. side scatter (SSC) area, and excluding doublets using FSC-area vs. FSC-height. The cells are assayed for FcɛRIα positive cells and further assessed for CD63 and CD203c expression. The percentage of CD63 positive basophils in the FcɛRIα positive and CD203c positive basophils is determined.
Regarding claims 2 and 6, the sample is a fluid, i.e. whole blood and the method includes lysing erythrocytes (p. 1332, Basophil Activation test).
Regarding claim 3, the method includes basophil activation induced by a test substance (p. 1332, Basophil Activation test).
Regarding claim 4, the test substance is an allergen (abstract, introduction p. 1331-1332, whole page).
Regarding claims 5 and 19, the test substance is an allergen, specifically a protein including the peanut allergens, oleosins Ara h 14/15 (p. 1332, isolation and purif. Section and basophil activation test section).
Regarding claims 7 and 20, the flow cytometry is conducted using two lasers, as the cytometer allows for forward and side scatter and basophil activation and the two lasers measure forward and side scatter and basophil identification and activation status. Further, the reference uses the BD LSR II flow cytometer which is a multilaser, multiparameter analysis cytometer. Additionally, regarding claim 20, the lasers are used to identify basophils according to the claimed antibodies and thus are taken to be configured for said measurements.
Regarding claim 8, the fluorochromes include PE, PE/Cy7 and APC (p. 1332, Basophil Activation test), which according to applicants’ specification (0105) are ones which have low spillover.
Regarding claims 9, 10, 11, the method for determining basophil activation includes a computer analysis method which includes obtaining flow cytometry data including forward and side scatter measurements, fluorescence of the mixture of antibodies including CD203c, CD63 and FcεRIα, and computing the data obtained from the cytometric method using the FCS express 5 software program and GraphPad Prism software package (p. 1332, Basophil Activation test, and see above cited claim limitation teachings).
Regarding claims 18 and 21, the method analyzes forward and side scatter data, and excluding doublets (Fig. E1).
Thus, the reference anticipates the claimed subject matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 1-11,17-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over EP2037269 (IDS) to Sainte-Laudy in view of Schwager et al. (J. Allergy Clin Immun., 2017, p. 1331-1338.e8, IDS).
Regarding claim 1, EP2037269 teaches a cytometric based method for determining basophil activation in a sample obtained from a subject comprising
a. providing a sample of said subject (0012-0014);
b. treating/stimulating the sample with a test substance (0012, 0022, for example);
c. adding a mixture of antibodies each labelled with a different fluorochrome, said mixture containing the labelled antibodies anti-CD63, anti-CD203c and anti-FcεRIα, and incubating said mixture with said sample (0012-0013, 0015, 0019, 0020, for example);
d. measuring the labelled sample obtained in step b) by flow cytometric based measurement (abstract, 0001, 0009, 0012, 0013, 0016, 0098, 0108-0109, 0118, for example) ;
e. determining basophil activation based on the analysis of the measured samples and obtained data by flow cytometry-based measurement, the analysis includes measuring basophil activation expressed as changes in fluorescence intensities based on the activation markers which include CD203c, CD63 and FcεRIα (0003, 0007, 0008,0012, 0013, 0015, 0020). Using flow cytometry, the reference teaches gating basophils which are CD63 positive (0109, Fig 1, 2) and FcεRIα positive (0111-0113, 0145, 0148, Fig. 11A) and using forward and side scatter data to exclude doublets and analyze CD63 positive cells (0116-0118).
Regarding claims 2 and 6, the sample is a fluid, i.e. blood or purified blood (0012, 0077,for example) and the method includes lysing erythrocytes (0013, step d)).
Regarding claim 3, the method includes basophil activation induced by a test substance (0012, 0016, for example).
Regarding claim 4, the test substance is a mitogen, an antigen, an allergen, a protein or peptide, a non-proteinaceous allergen, a low molecular weight allergen or drug or a hapten (0022).
Regarding claims 5 and 19, the test substance is an allergen including pharmaceuticals (0024), inhalant (0110, for example), a food allergen (0068), insect allergens (0074) and nut allergens (0074).
Regarding claims 7 and 20, the flow cytometry is conducted using two lasers, i.e. an argon laser and a red laser (0116) and the two lasers measure forward and side scatter and basophil activation (0116-0118, for example). Additionally, regarding claim 20, the lasers are used to identify basophils according to the claimed antibodies and thus are taken to be configured for said measurements.
Regarding claim 8, the fluorochromes include PE and APC (0116), which according to applicants’ specification (0105) are ones which have low spillover.
Regarding claims 9, 10, 11, the method for determining basophil activation includes a computer analysis method which includes obtaining flow cytometry data including forward and side scatter measurements, fluorescence of the mixture of antibodies including CD203c, CD63 and FcεRIα (0003, 0007, 0008,0012, 0013, 0015, 0020), and computing the data obtained from the cytometric method (0099, 0108, 0109, 0118, 0119, for example and see above cited claim limitation teachings).
Regarding claim 17, the blood sample to be analyzed is stored at room temperature for up to 72 hours and thus, falls within applicants “up to 7 days” which is interpreted to include storage for any time less than or equal to 7 days (0124). EP269 also teaches storage between 2-8°C for up to 72 hours (0124-0126).
While the reference teaches using a mixture of antibodies including CD203c, CD63 and FcεRIα, gating using side scatter, forward scatter and fluorescence to analyze the percentage of CD63 positive basophils, the analysis examples of the reference do not specifically teach gating for basophils being double positive for CD203c and FcεRIα, excluding doublets, analyzing said double positive cells based on forward and side scatter and then further analyzing said cells for expression of CD203c versus CD63 according to claims 1 and 10, 18, 21.
Schwager teaches a flow cytometry-based basophil activation test (BAT) comprising obtaining a blood sample, treating the sample with a test substance, i.e a peanut allergen, specifically peanut oleosins Ara h 14/15, adding a mixture of antibodies each labelled with a different fluorochrome, i.e., PE/Cy7 FcɛRIα, PECD203c, and APC CD63 and measuring the labelled sample using flow cytometry to determine basophil activation based upon antibody labelling. The CD63 positive percentage of CD203c positive cells were calculated (p. 1332, Basophil Activation test). The flow cytometric gating strategy for BAT is shown in Fig. E1 p. 1338.e2, which shows forward scatter (FSC) area vs. side scatter (SSC) area, and excluding doublets using FSC-area vs. FSC-height. The cells are assayed for FcɛRIα positive cells and further assessed for CD63 and CD203c expression. The percentage of CD63 positive basophils in the FcɛRIα positive and CD203c positive basophils is determined. he method for determining basophil activation includes a computer analysis method which includes obtaining flow cytometry data including forward and side scatter measurements, fluorescence of the mixture of antibodies including CD203c, CD63 and FcεRIα, and computing the data obtained from the cytometric method using the FCS express 5 software program and GraphPad Prism software package (p. 1332, Basophil Activation test, and see above cited claim limitation teachings).
Regarding claims 18 and 21, the method analyzes forward and side scatter data, and excluding doublets (Fig. E1).
Thus, before the effective filing date of the claimed invention, the prior art references (EP’269 and Schwager) teach flow cytometric based methods and data analysis methods for determining basophil activation. The art recognizes cell surface markers and antibodies specific for said markers which are indicative of an allergic response and specific for basophils and their activation, i.e. CD63, CD203c and FcɛRIα, and gating to detect side scatter, forward scatter and fluorescence to determine the percentage of CD63 positive basophils; however Schwager’s gating method allows one to more specifically sort, gate and identify activated basophils expressing cell surface markers indicating an allergic response. Therefore, one of ordinary skill in the art would have been motivated to combine the prior art references to the achieve the claimed invention, and there would have been a reasonable expectation of successfully determining basophil activation using the combined methods of the prior art.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over EP2037269 (IDS) to Sainte-Laudy in view of Schwager et al. (J. Allergy Clin Immun., 2017, p. 1331-1338.e8, IDS) as applied to claims1-11,17-21 above, and further in view of Arif-Lusson et al. (J. Immunol. Methods, 481-482, p. 1-8, May 2020).
The teachings of EP’269 and Schwager are found above.
The above references do not teach sample processing and measurement using a flow cytometer with integrated robotic sample handling according to claim 16.
Arif-Lusson teaches automation of sample preparation in a basophil activation test, wherein blood samples are mixed with antibodies including CD203c-PE and CD63-PB, after incubation erythrocytes are lysed and the samples are analyzed by flow cytometry. ABiomek NXP robotic platform is used for automation and both CD203c and CD63 levels are monitored for basophil reactivity in allergic and non-allergic donor blood sample (abstract, p. 3, section 2.2) and data is analyzed using a computer software program (p. 3, section 2.3). The allergens used in the samples include food, protein and peanut allergens (p. 3, section 2.1). The reference teaches that the sample automation reduced hands-on time to as little as 5 minutes and allows for very low intra-assay and inter-operator variability without impairing performance characteristics (p. 7, section 4, Discussion 1st and 2nd parag.).
Therefore, before the effective filing date of the clamed invention, one of ordinary skill in the art would have been motivated by the teachings of Arif-Lusson to use a flow cytometer having an integrated robotic sample handling in the methods of EP’269 and Schwager because the reference teaches that the use of robotic sample handling results in an improved BAT cytometric method by reducing hands-on time to as little as 5 minutes and allowing for very low intra-assay and inter-operator variability without impairing performance characteristics.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schwager et al. (J. Allergy Clin Immun., 2017, p. 1331-1338.e8, IDS) as applied to claims 1-11, 18-21 above, and further in view of Arif-Lusson et al. (J. Immunol. Methods, 481-482, p. 1-8, May 2020).
The teachings of Schwager are found above.
The above references do not teach sample processing and measurement using a flow cytometer with integrated robotic sample handling according to claim 16.
Arif-Lusson teaches automation of sample preparation in a basophil activation test, wherein blood samples are mixed with antibodies including CD203c-PE and CD63-PB, after incubation erythrocytes are lysed and the samples are analyzed by flow cytometry. ABiomek NXP robotic platform is used for automation and both CD203c and CD63 levels are monitored for basophil reactivity in allergic and non-allergic donor blood sample (abstract, p. 3, section 2.2) and data is analyzed using a computer software program (p. 3, section 2.3). The allergens used in the samples include food, protein and peanut allergens (p. 3, section 2.1). The reference teaches that the sample automation reduced hands-on time to as little as 5 minutes and allows for very low intra-assay and inter-operator variability without impairing performance characteristics (p. 7, section 4, Discussion 1st and 2nd parag.).
Therefore, before the effective filing date of the clamed invention, one of ordinary skill in the art would have been motivated by the teachings of Arif-Lusson to use a flow cytometer having an integrated robotic sample handling in the method of Schwager because the reference teaches that the use of robotic sample handling results in an improved BAT cytometric method by reducing hands-on time to as little as 5 minutes and allowing for very low intra-assay and inter-operator variability without impairing performance characteristics.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 3-6, 9, 10, 11, 16, 18, 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 5, 6, 7, 11, 12, 13, 18, 19 of copending Application No. 19492015 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed inventions are drawn to cytometric based and computer-implemented methods for determining basophil activation wherein fluid samples are labeled with fluorescently-labelled antibodies to CD63, CD203c and FcεRIα, measuring and determining basophil activation data induced by an allergen by flow cytometry and gating using forward and side scatter data, analyzing cells positive for both CD203c and FcεRIα, and determining the percentage of CD63 positive cells. Although the reference claims include additional steps not required by the instant examined claims, the examined claims are drawn to a method comprising and thus not excluding additional method steps. Therefore, the examined claims would have been obvious over the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY MAUREEN GOUGH whose telephone number is (571)272-0697. The examiner can normally be reached M-Thu 8-5.
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/TIFFANY M GOUGH/ Examiner, Art Unit 1651
/MELENIE L GORDON/ Supervisory Patent Examiner, Art Unit 1651