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.
Status of the Claims
Claims 11-14, and 16-25 are pending and examined herein. Claims 1-10 and 15 are cancelled.
Priority
This application, 18/578,165, filed 01/10/2024, is a 371 of PCT/EP2022/069942 filed on 07/15/2022, and claims benefit of EP21306004.9 filed on 07/16/2021. This priority is acknowledged and the claims examined herein are treated as having an effective filing date of 07/16/2021.
Information Disclosure Statement
The Information Disclosure Statement filed 01/10/2024 is acknowledged and has been considered.
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 16, 17, and 19 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.
Claims 16, 17, and 19 recite “…at a first specific time…” and “at a second specific time”. The claims are indefinite because there are multiple possible conflicting interpretations based on the claim language provided. For example, it is unclear if the claim language is to be interpreted as the first and second sample are collected at the same time of day on the respective calendar day the sample is taken (e.g. 8:00 a.m.), or whether the recited “specific time” is representative of when the before/during treatment samples are taken in relation to the start of the treatment (e.g. 10 days before and 10 days after the start of treatment). As there are multiple potential conflicting interpretations of the claim language, these claims are indefinite.
Additionally, claim 16 recites “…administering to the subject a different and/or increased amount of a treatment…”. However, the claim is indefinite because it is unclear if the recited “different” is to be interpreted as administering a different amount of treatment, or a different treatment entirely.
Appropriate 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.
Claims 11-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by "SEA412Hu 96 Tests Enzyme-linked Immunosorbent Assay Kit For Alpha- Hemoglobin Stabilizing Protein (aHSP) Organism Species: Homo sapiens (Human)", Instruction Manual, 1 May 2016, pages 1-9, XP055853434, Retrieved at (https://www.cloud-clone.com/manual/ELISA-Kit-for-Alpha-Hemoglobin-Stabilizing-Protein-(aHSP)-SEA412Hu.pdf), (herein referred to as Cloud-Clone).
Regarding claims 11 and 12, Cloud-Clone teaches a kit and in vitro method for determining the concentration of AHSP in human serum, plasma, cell lysates and other biological fluids via ELISA assay (page 1, paragraph "intended use"; page 6, paragraph “detection range”). More specifically, Cloud-Clone teaches the use of a microplate that has been pre-coated with an antibody specific to aHSP, where standards or samples are then added to the appropriate microplate wells with a biotin-conjugated antibody specific to aHSP (page 5, paragraph “Test Principle”). Cloud-Clone also teaches that the concentration of AHSP is determined by spectrophotometry which measures the signal intensity of avidin linked to the biotin-conjugated anti-AHSP antibody after addition of a substrate (page 5, paragraph “Test Principle”). The concentration of AHSP in the sample is consequently calculated by comparing the optical density to a standard curve (page 5, paragraph "Test Principle"). Therefore, the signal intensity measured represents the amount of bound anti-AHSP antibodies.
Regarding claim 13, Cloud-Clone teaches that the sample is first contacted with the capture antibody, and then with the detecting antibody. Specifically, Cloud-Clone teaches that samples are first added into the microplate provided that has been pre-coated with an antibody specific to aHSP (page 4, “Assay Procedure”, lines 1-3; page 5, paragraph “Test Principle”). Cloud-Clone then teaches that the detection reagent A is added (page 4, paragraph "assay procedure", line 5) which can only be the biotin-conjugated antibody as it is described in the paragraph "test principle" (page 5, paragraph "test principle", lines 1-2).
Regarding claim 14, Cloud-Clone teaches that the Detection Reagent B is added after the addition of Detection Reagent A (page 4, paragraph "assay procedure", line 12). As described in the "Test Principle" paragraph, this reagent can only be the protein avidin which is conjugated to the enzyme horseradish-peroxidase (HRP) (page 5, paragraph "test principle". lines 2-3).
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 16-20 and 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Baudin-Creuza et al. (US 9,494,603 B2), (herein referred to as Baudin-Creuza) in view of Cappellini et al. (2020). “A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia”. New England Journal of Medicine, 382(13), 1219-1231, (herein referred to as Cappellini), and Basu et al. (2013). “2D DIGE based proteomics study of erythrocyte cytosol in sickle cell disease: Altered proteostasis and oxidative stress”. Proteomics, 13(21), 3233-3242. (herein referred to as Basu).
Regarding claims 16, 17, and 18, Baudin-Creuza teaches a method for diagnosing, staging and/or monitoring a hemoglobin-related disorder such as β-thalassemia or a treatment against said hemoglobin-related disorder in a subject in need thereof based on the detection and/or quantification the presence of free α-Hb pool in a biological sample obtained from said subject (abstract). More specifically, Baudin-Creuza teaches contacting blood samples obtained from a subject, before and after administration of a treatment to said subject, with Alpha-Hemoglobin Stabilizing Protein (AHSP) to bind free monomeric alpha hemoglobin (α-Hb), detecting and/or quantifying the presence of AHSP-bound free monomeric α-Hb in said blood samples, and correlating said amount of the AHSP-bound free monomeric α-Hb with monitoring of a treatment against said hemoglobin disorder in said subject (claim 1, paragraph 20, lines 6-16). Additionally, Baudin-Creuza teaches the treatment against said haemoglobin disorder is treatment with iron, treatment with erythropoietin, treatment with cobalamin, or treatment with Y chain synthesis stimulating agent (claim 7, paragraph 20, lines 53-58). Lastly, Baudin-Creuza teaches that their method allows for monitoring of the evolution of the imbalance of Hb synthesis in response to treatments, and allows for fine adjustments of the therapy (paragraph 16, lines 50-54).
Regarding claim 16, Baudin-Creuza teaches that the treatment is determined to be ineffective when the amount of the AHSP-bound free monomeric α-Hb quantified in the subject after administration of the treatment is the same or increased as compared to the amount in the subject before administration of treatment (claim 1, paragraph 20, lines 26-34).
Regarding claim 17, Baudin-Creuza teaches that the treatment is determined to be effective when the amount of the AHSP-bound free monomeric α-Hb quantified in the subject after administration of the treatment is decreased as compared to the amount in said subject before administration of said treatment (claim 1, paragraph 20, lines 16-24).
Regarding claim 18, Baudin-Creuza teaches that the amount of free α-Hb quantified can be compared with the corresponding amount detected in the samples of control subjects, in previous samples obtained from the subject, or with normal reference values (column 4, lines 61-64).
However, Baudin-Creuza does not teach that the biomarker being measured in the patient sample is AHSP, nor does Baudin-Creuza specifically teach altering the treatment by administering a different and/or increasing the amount of treatment or continuing the treatment based on the comparison of the biomarker levels from the second sample compared to the first sample.
Basu teaches a proteomics study of erythrocyte cytosol in sickle cell disease (abstract). Specifically, Basu teaches the measurement of AHSP levels in blood samples taken from both sickle cell patients and healthy volunteers (page 3234, column 2, 1st full paragraph; page 3234, column 2, 2nd full paragraph). Basu teaches that AHSP levels are upregulated in sickle cell patients compared to healthy controls (page 3237, column 1, 1st paragraph).
Cappellini teaches a clinical trial where patients with transfusion-dependent β-thalassemia were administered the treatment luspatercept (a recombinant fusion protein that enhances late-stage erythropoiesis) or a placebo for 48 weeks (abstract; column 1, 3rd paragraph). Specifically, Cappellini teaches that patients receiving luspatercept could have the treatment dose-titrated up from 1.0 mg/kg to 1.25 mg/kg during the treatment periods based on a clinical variable level in comparison to the patient’s previous levels (Supplemental Materials – Protocol, page 65, “Dose Titration”). Additionally, Cappellini teaches that patients receiving luspatercept could be administered a dose reduction based on the change in mean Hb level when compared to to the Hb level prior to the last luspatercept dose, e.g. when there is an increase in Hb >2.0 g/dL, dose is reduced by 25% (Supplemental Materials – Protocol, page 66, “Dose Delay and Dose Reduction”; Table 5).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of diagnosing, staging and/or monitoring a hemoglobin-related disorder or the treatment for the disorder in a patient by quantifying a biomarker in a patient sample, as taught by Baudin-Creuza, to measure AHSP as the biomarker, as disclosed by Basu, as a matter of simple substitution within inventions in the same field. Baudin-Creuza teaches that free α-Hb can be used as a biomarker for diagnosing, staging and/or monitoring a hemoglobin-related disorder, and Basu also teaches that increased levels of AHSP act as a biomarker of hemoglobin-related disorder (sickle cell). Therefore, as both these biomarkers were measured in blood samples using quantification techniques well known in the art, one of ordinary skill could have substituted the measurement of α-Hb for AHSP and the results would have been predictable.
It also would have been obvious to modify the method of Baudin-Creuza to alter the administration of treatment based on a clinical variable level in comparison to the patient’s previous levels, as taught by Cappellini, as it would be “obvious to try”. There are a limited number of reasons why a patient’s levels of a biomarker would be measured during the course of receiving treatment and compared against previous levels. Making such comparisons to monitor a patient’s response to a treatment in order to know when/how to make treatment adjustments are often necessary from a clinical perspective, and is a practice that is well-understood, routine and conventional in the field.
A skilled artisan would have been motivated to make these modifications to the method taught by Baudin-Creuza because in addition to acting as a biomarker for diagnosing, staging and/or monitoring a hemoglobin-related disorder, by measuring AHSP instead of α-Hb in the method, it may allow for the additional application of differential diagnosis of hemoglobin-related disorder type, as Basu teaches that AHSP expression was higher in patients with sickle cell anemia versus thalassemia (attract). Furthermore, the motivation to alter the administration of treatment based on a clinical variable level in comparison to the patient’s previous levels, as taught by Cappellini, would be to optimize treatment usage for better patient outcomes.
Regarding claim 19, Cappellini teaches that the initial concentration of biomarkers is determined in samples taken during the screening/run-in period which runs from 12 weeks before the first treatment dose to the day before the first treatment dose (Supplemental Materials – Protocol, page 47-51, Table 3). Cappellini teaches that serious/severe adverse events experienced during this 12-week period can lead to a screen failure and the patient will be excluded from the study, and that hospitalization or prolonged hospitalization qualifies as a serious/severe adverse event (Supplemental Materials – Protocol, page 47-51, Table 3; page 63, “Screen Failures”; page 83-84). Furthermore, Cappellini teaches the study exclusion criteria which includes, DVT or stroke requiring medical intervention ≤ 24 weeks prior to randomization, use of an erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to randomization, uncontrolled hypertension, major organ damage, major surgery ≤ 12 weeks prior to randomization, any condition including the presence of laboratory abnormalities which places the subject at unacceptable risk if he/she were to participate in the study.
Regarding claim 20, Baudin-Creuza teaches that the haemoglobin-related disorder is beta-thalassaemia (abstract).
Regarding claims 22 and 23, Baudin-Creuza teaches that the concentration is determined by a sandwich ELISA (column 10, lines 48-56).
Regarding claims 24 and 25, Baudin-Creuza teaches that the sample is a red blood cell sample, specifically a red blood cell lysate (“hemolysate”, column 15, lines 29-40).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Baudin-Creuza et al. (US 9.494,603 B2), in view of Cappellini et al. (2020) and Basu et al. (2013) as applied to claims 16-20 and 22-25 above, and further in view of Watanapokasin et al. (2005). “In vivo and in vitro studies of fetal hemoglobin induction by hydroxyurea in β-thalassemia/hemoglobin E patients”. Experimental Hematology, 33(12), 1486-1492, (herein referred to as Watanapokasin).
The teachings of Baudin-Creuza in view of Cappellini and Basu are incorporated herein.
Regarding claim 21, Baudin-Creuza in view of Cappellini and Basu recites all of the limitations of claim 18 of the application but does not recite wherein the treatment of the haemoglobin- related disorder is hydroxycarbamide.
However, Watanapokasin teaches in vivo and in vitro studies of fetal hemoglobin induction by hydroxyurea in β-thalassemia/hemoglobin E patients (abstract). More specifically, Watanapokasin teaches that β-thalassemia/hemoglobin E (β-thal/HbE) patients were treated with hydroxyurea orally for 2 years (abstract). The results showed that 30 μM hydroxyurea increased HbF with minimal cytotoxic effects in both normal adults and β-thal/HbE patients (page 1491, column 1, 1st paragraph).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Baudin-Creuza in view of Cappellini and Basu to use hydroxycarbamide as the treatment of the haemoglobin-related disorder, as taught by Watanapokasin, as it would be “obvious to try” because there are a limited number of effective and well-studied treatments for haemoglobin-related disorders. A skilled artisan would have been motivated to make this modification because Watanapokasin teaches not only that hydroxycarbamide treatment increased the fractional HbF content in b-Thal/HbE patients, but also recites that hydroxyurea seems to be the most effective and has now been tested in large multicenter trials for patients with sickle cell disease (page 1486, column 2, 1st paragraph).
Conclusion
For all the reasons discussed above, claims 11-14 and 16-25 are rejected and therefore no claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER JOSEPH HOFFMAN whose telephone number is (571)272-9080. The examiner can normally be reached 10:00-6:30 M-F.
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/ALEXANDER J. HOFFMAN/ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/ Supervisory Patent Examiner, Art Unit 1677 June 16, 2026
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