DETAILED ACTION
Status of the Application
Claims 1-10 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A preliminary amendment of claim 1 as submitted in a communication filed on 1/26/2024 is acknowledged.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119
(a)-(d). to KOREA 10-2023-0145128 filed 10/25/2023. Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file. The instant application is a 371 national stage application of PCT/KR2023/019612 filed on 11/30/2023.
Specification
The disclosure is objected to because of the following informalities: Paragraph [0027] is objected to in the recitation of “anti-MOP”. To enhance clarity, the term should be amended to “anti-MPO”. Appropriate correction is required.
Claim Objections
Claim 5 is objected to because of the following informalities: step (a) recites "anti-MOP antibody". To enhance clarity, the term should be amended to “anti-MPO antibody”. Appropriate correction is required.
Claim 8 is objected to in the recitation of “Alexa Fluor-355”. Alexa Fluor-355 is not offered by ThermoFisher Scientific. ThermoFisher Scientific offers Alexa Fluor 350 and if this is what was meant, please amend. Appropriate correction is required.
Claim 8 is objected to in the recitation of “Alexa Fluor 780”. Alexa Fluor 780 is not offered by ThermoFisher Scientific. ThermoFisher Scientific does offer Alexa Fluor 790 and if this is what was meant, please amend. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 3 and 8 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.
Claim 3 is indefinite in the recitation of “a subject without an acute exacerbation state within three weeks” for the following reasons. One cannot determine if the method requires “a subject that does not have acute exacerbation of bronchiectasis for 3 weeks in a row” or “a subject that does not have acute exacerbation of bronchiectasis for 1 day to 3 weeks in a row” or “a subject without acute exacerbation of bronchiectasis”. Correction is required.
Claim 8 is indefinite in the recitation of “PicoGreen” and “RiboGreen” for the following reasons. It is unclear how one would use PicoGreen or RiboGreen as a fluorescent element to detect protein concentration because neither fluoresce with protein-protein interactions. PicoGreen intercalates into dsDNA helix and RiboGreen binds to RNA. Correction is required.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claim 9 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Parekh et al. (US-2017/0108511 A1, published 04/20/2017), as evidenced by Bheemavarapu et al. (2019 41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Berlin, Germany, 2019, pp. 5447-5450).
Claim 9 is directed to a kit for diagnosing acute exacerbation of bronchiectasis, comprising a membrane coated with an anti-MPO antibody or an antibody fragment thereof, in the form of a cartridge for immunofluorescence measurement.
Parekh et al. teaches a portable kit that uses cartridges to determine the levels of urinary markers. (see pg. 22, paragraph [0239]). Parekh et al. teaches the determination of urinary markers, wherein one of the markers is myeloperoxidase (MPO), in subjects suffering from a respiratory disorder (see claims 35,38). Parekh et al. teaches the concentration of a marker (MPO) may rely upon a binding agent such as an antibody that binds specifically to the marker of interest (see pg. 4, paragraph [0044]). Parekh et al. teaches testing devices that have a solid support that can be a membrane material that has a binding reagent (see pg. 23, paragraph [0242]). Parekh et al. further teaches the use of a further reagent (antibody) that binds to a complex of fluorescent labeled binding reagent (antibody) and the marker (see pg.23, paragraph [0242] – [0243]). The cartridges of Parekh et al. used to determine the concentration of MPO, would have an antibody against MPO and would inherently have membranes as evidenced by Bheemavarapu et al. (see pg. 5448, Fig. 1 and Principle of Operation). While claim 9 states that the kit is for diagnosing acute exacerbation of bronchiectasis, it is noted that this is an intended use. The patentability of a product is determined solely by its characteristics. Since the kit comprising the cartridge of Parekh et al. comprises all of the elements required by claim 9, the kit of Parekh et al. as evidenced by Bheemavarapu et al. anticipates claim 9 as written/interpreted.
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.
Claim(s) 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Sloane et al. (WO-2007/140508 A1, published on 12/13/2007) in view of Parekh et al. (US-2017/0108511 A1, published 04/20/2017), in further view of Rosengren et al. (Eur Respir J 2022:60:Suppl. 66, 2017.; Abstract: presented at 2022 ERS International Congress and Bedi et al. (Am J Respir Crit Care Med.10/01/2018).
Regarding Claims 1-4, Sloane et al. teaches the detection of myeloperoxidase (MPO) in sputum samples from cystic fibrosis patients that have been treated for an acute clinical exacerbation using a two-site ELISA (Example 1, pg. 65, Example 20, pg. 99, lines 10-29). Sloane et al. further teaches that subjects that suffered from clinical exacerbation had considerably higher levels of MPO detected than control subjects (Example 20, pg. 99, lines 31-36). Sloane et al. further teaches that clinical exacerbation suffered by a CF patient is correlated to bronchiectasis (pg. 54, line 20-22, pg. 59, line 24-26). Sloane et al. further teaches that detection of reduced levels of protein or loss of protein expression for neutrophil derived proteins indicates that the subject is recovering from an exacerbated state (see pg. 48, lines 25-34). Sloane et al. does not teach the 50 ng/mL MPO concentration threshold for determination of acute exacerbation state of bronchiectasis. Sloane et al. does not specifically teach diagnosing an acute exacerbation of bronchiectasis in a subject without an acute exacerbation state within three weeks.
Parekh et al. teaches the determination of myeloperoxidase (MPO) levels in urine samples of subjects suffering from a respiratory disorder (see claims 35,38), where the respiratory disorder can be bronchiectasis (see paragraph [0027]). Parekh et al. further teaches threshold levels of markers in urine such as MPO, were taken from subjects where the subject was not suffering from an exacerbation of inflammation. An exacerbation was identified based on observance of statistically significant deviation from the baseline set at non-exacerbation levels (see paragraph [0165]). Parekh et al. does not teach the 50 ng/mL MPO concentration threshold for determination of acute exacerbation state of bronchiectasis from sputum samples. Parekh et al. does not teach a subject without acute exacerbation state within three weeks.
Rosengren et al. teaches sputum samples from COPD patients had highly variable MPO concentrations (39 to 65,000 ng/mL) with increased sputum MPO concentration associated with an increased risk of exacerbation (See paragraph 3). Rosengren et al. teaches taking samples from the same patient at different time points to see if there is a correlation between MPO concentration and exacerbation. Rosengren et al. does not teach diagnosing acute exacerbation of bronchiectasis.
Bedi et al. teaches studying patients with no infective exacerbation of bronchiectasis for at least 4 weeks before taking samples (see methods, paragraph 1). Bedi et al. teaches that MPO is present at significantly higher concentration in severe bronchiectasis patients compared to mild bronchiectasis patients and a normal control group (see pg. 883, Blood Neutrophil: Degranulation and Reactive Oxygen Species Generation). Bedi et al. does not teach the 50 ng/mL MPO concentration threshold for determination of acute exacerbation state of bronchiectasis.
Claims 1-4 are directed to a method for diagnosing acute exacerbation of bronchiectasis by measuring the myeloperoxidase (MPO) concentration in biological samples. Claim 2 adds the subject is a subject suffering from bronchiectasis. Claim 3 adds a subject without an acute exacerbation state within three weeks. Claim 4 adds the biological sample is sputum. An acute exacerbation state of bronchiectasis was measured with a MPO concentration exceeding 50 ng/mL.
It would have been obvious to one of ordinary skill in the art before the effective filling date of the claimed invention to diagnose acute exacerbation of bronchiectasis by taking sputum samples from the cystic fibrosis subjects in Sloane et al. that are suffering from acute exacerbation of bronchiectasis and from patients that are no longer suffering from acute clinical exacerbation as a baseline as taught in Parekh et al. and Bedi et al., within the range of MPO concentrations taught in Rosengren et al. to determine a MPO concentration threshold such as 50 ng/mL. A person of ordinary skill in the art is motivated to take sputum samples of subjects with acute exacerbation of bronchiectasis as taught in Sloane et al. and samples from subjects no longer suffering from acute exacerbation as taught in Parekh et al. because Rosengren et al. teaches that higher concentration of MPO is correlated to higher risk of exacerbation. While none of the references teach measuring the MPO concentration on a subject without an acute exacerbation state within three weeks, one skilled in the art would take protein concentrations at different time points as taught by Rosengren et al. and Bedi et al. to see if there is a significant difference in concentrations to see if the protein is a reliable marker for diagnosing acute bronchiectasis. One of ordinary skill in the art has a reasonable expectation of success in diagnosing acute exacerbation of bronchiectasis by taking the sputum samples from patients with acute clinical exacerbation of bronchiectasis taught in Sloane et al. and the subject samples of patients no longer suffering from an exacerbation state as taught in Parekh et al., and comparing their MPO concentration to establish a baseline because Rosengren et al. teaches that when the MPO concentration in a range of 39 to 65,000 ng/mL goes up, there is an increase in the risk of exacerbation. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding Claims 5-8, Sloane et al teaches a two-site ELISA to determine the amount of myeloperoxidase in a sputum sample with an anti-human myeloperoxidase monoclonal antibody and a rabbit anti-human myeloperoxidase polyclonal antibody (see pg. 99, Example 20). Sloane et al. also teaches a FLISA where one of the antibodies can be labeled with a fluorescent label (e.g. FITC or Texas Red) (see pg. 25, line 5-9) and used to detect the protein that is bound to tan antibody that is immobilized on a membrane (see pg. 25, line 26-29). Sloane et al. further teaches measuring myeloperoxidase levels in liquified sputum by dilution if the sample in a blocking buffer at 1/50 (see pg. 99, Example 20, line 15-16). Sloane et al. does not teach a sample diluted with a dilution buffer at a volume ratio of 1:5 (v/V) to 1:20 (v/v).
Parekh et al. teaches diluting biological samples (wound sample) 1 in 20 in MMP buffer (Example 4, paragraph [0593], Step 1). Parekh et al. teaches concentration of marker is determined using an antibody conjugated to a label that can be a fluorophore (see paragraph [0046]). Parekh et al. further teaches a solid support such as a membrane where an antibody is bound to test urine samples (see paragraphs [0242] - [0243]). Parekh et al. does not teach specific fluorophores or fluorescent dyes.
Bedi et al. teaches the use of fluorescent dyes (Alexa Fluor) with antibodies (see page 881, Neutrophil Activation).
Claims 5-8 are directed to a method of measuring MPO concentration in biological samples with a detection buffer with a fluorescent labeled anti-MPO antibody and reacted with a membrane coated with a secondary anti-MPO antibody. Claim 6 adds the biological sample is diluted before measurement of MPO concentration. Claim 7 adds that the dilution is at a volume ratio of 1:5 (v/v) to 1:20 (v/v). Claim 8 adds the fluorescent element is one selected from a list of fluorescent dyes.
It would have been obvious to one of ordinary skill in the art before the effective filling date of the claimed invention to measure the concentration of MPO in a biological sample using an anti-MPO antibody with a fluorophore and a second anti-MPO antibody attached to a membrane as taught in Sloane et al. While Sloane et al. dilutes sputum samples at 1/50, one of ordinary skill in the art would be motivated to test out different dilutions such as 1:5 to 1:20 (v/v) on different biological samples depending on the type of sample because it is known in the art as evidenced in Parekh et al. that different biological samples require different dilutions for detection of proteins. Although no reference teaches using all of the fluorescent elements in claim 8, Sloane et al. and Parekh et al. teach the use of fluorophores for detection. One of ordinary skill in the art has a reasonable expectation of success at determining the protein concentration of MPO in biological samples by using a diluted sample in a method requiring a first anti-MPO antibody with a fluorescent element and a second anti-MPO that coats a membrane to help diagnose acute exacerbation of bronchiectasis because Sloane et al. teaches a similar method but with a higher dilution on sputum samples. It would require routine optimization based per biological sample to obtain results to detect the concentration of myeloperoxidase using a fluorescent method as described. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Parekh et al. (US-2017/0108511 A1, published 04/20/2017) in view of Bheemavarapu et al. (2019 41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Berlin, Germany, 2019, pp. 5447-5450).
The teachings of Parekh et al. have been discussed above. Parekh et al. does not teach a cartridge with a nitrocellulose membrane.
Bheemavarapu et al. teaches cartridges with nitrocellulose membranes that have pre-fabricated antigens or antibodies that are fluorescence labeled (see pg. 5448, Fig. 1 and Principle of Operation).
Claim 10 is directed in part to a kit for diagnosing acute exacerbation of bronchiectasis, comprising a nitrocellulose membrane coated with an anti-MPO antibody or an antibody fragment thereof, in the form of a cartridge for immunofluorescence measurement.
[It would have been obvious to one of ordinary skill in the art before the effective filling date of the claimed invention to use a nitrocellulose membrane in the cartridge of Parekh et al. A person of ordinary skill in the art is motivated to use a nitrocellulose membrane in the cartridge of Parekh et al. because as known in the art, and taught by Bheemavarapu et al., cartridges commonly have nitrocellulose membranes wherein the desired antibody for detection of the intended target is attached to. One of ordinary skill in the art has a reasonable expectation of success at using a nitrocellulose membrane in a cartridge because Bheemavarapu et al. teach the use of nitrocellulose membranes in cartridges. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DALTON EDWARD KIEFER whose telephone number is (571)272-1235. The examiner can normally be reached M-F 7:30-5 EST.
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/DALTON EDWARD KIEFER/Examiner, Art Unit 1652
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652