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 1-3, 5, 6, 8-12, and 14-19 are pending and examined herein. Claims 4, 7, and 13 are cancelled.
Priority
This application, 18/559,281, filed 11/06/2023, is a 371 of PCT/EP2022/062375 filed on 05/06/2022, and claims benefit of EP21382416.2 filed on 05/07/2021. This priority is acknowledged and the claims examined herein are treated as having an effective filing date of 05/07/2021.
Information Disclosure Statement
The Information Disclosure Statement filed 10/09/2025 is acknowledged and has been considered.
Claim Objections
Claims 1, 2, 11, and 12 are objected to because of the following informalities:
Claims 1, 2, 11, and 12 are objected to due to the use of square brackets when reciting Gal-3 and FABP4 in the claims (i.e. “[Gal-3 and FABP4]”). Such use of brackets is generally for the designation of subject matter to be deleted from the claim, and therefore, it is suggested that these brackets be removed from the claims for the purposes of clarity.
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application also includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are:
“A kit comprising: a. means, reagents or tools for obtaining… …from the patients, b. means, reagents or tools for measuring the concentration level of at least [Gal-3 and FABP4], and c. means, reagents or tools for determining the AF type.” in claims 11 and 12.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
The specification does not define the means by which the kit is used to obtain a minimally-invasive sample from the patients, measure the concentration level of Gal-3 and FABP4, and determine the AF type. While, the specification recites the use of commercially available kits to measure Gal-3 and FABP4 (page 8, lines 4-10), this is not clearly linked to the function or kit of claims 11 and 12.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
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 11 and 12 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 limitation “…means, reagents or tools…” invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. The specification merely recites the function and does not identify any specific structure that is comprising a kit used for obtaining a minimally-invasive sample such as plasma, blood or serum from the patients, measuring the concentration level of Gal-3 and FABP4, and determining the AF type. Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Claims 1-3, 5, 6, 8-10, and 14-19 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 1 and 2 recite “…b) determining the AF type…”. However, the recited language of “determining” is indefinite because it is unclear what observations will be made to determine what type of AF the patient has, which could be done in several ways. For example, the “determining” could be done by observing the patients Gal-3 and FABP4 concentration level, or by simply reading a patient’s chart.
Furthermore, claims 1 and 2 also recite “…processing the concentration level values of [Gal-3 and FABP4] and the AF type in order to obtain a risk score…”, however, it is unclear how and what kind of processing is performed to determine the risk score given the information in the claim. The claims are indefinite because there are multiple possible conflicting interpretations based on the claim language. For example, it is unclear if the continuous Gal-3 and FABP4 data is subject to a method such as a log transformation or normalization, or whether the value is transformed into an integer value based on a determined range and subtracted or added to a value assigned to AF type.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 5, 6, 8-10, and 14-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception and a law of nature without significantly more. Claim 1 recites “An in vitro method for predicting the response of patients suffering from atrial fibrillation (AF) to catheter ablation treatment which comprises: a) measuring the concentration level of at least Gal-3 and FABP4 in a biological sample obtained from the patient, b) determining the AF type, c) processing the concentration level values of Gal-3 and FABP4 and the AF type in order to obtain a risk score and c) wherein if the risk score obtained in the step b) is higher than a pre-established reference, is an indication that the patient will not respond to catheter ablation treatment”. Claim 2 recites “An In vitro method for the prognosis of patients suffering from atrial fibrillation (AF} which comprises: a) measuring the concentration level of Gal- 3 and FABP4 in a biological sample obtained from the patient, b) determining the AF type, c) processing the concentration level values of Gal-3 and FABP4 and the AF type in order to obtain a risk score and c) wherein if the risk score obtained in the step b) is higher than a pre-established reference, is an indication that the patient has a bad prognosis, wherein bad prognosis indicates the presence of underlying fibrotic scar and arrhythmia recurrence after catheter ablation treatment”.
The steps are judicial exceptions because they are abstract ideas, specifically, mental processes that can be performed in the human mind, and/or are merely observing naturally occurring correlations (laws of nature/natural correlation). These judicial exceptions are not integrated into a practical application because there is no practical application recited in the claims such as performing a treatment in a way that is particular, and not merely instructions to "apply" the exception in a generic way. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps amount to mere data gathering that does not go beyond well-understood, routine, and conventional activity; as detailed below.
Step 1 – Whether a claim is to a statutory category - YES
The invention of claim 1 is directed to a method for predicting the response of patients suffering from AF to catheter ablation treatment by measuring Gal-3 and FABP4 in a sample, determining a risk score, and comparing that risk score to a reference to determine the patient’s response to treatment. Similarly, the invention of claim 2 is directed to a method for the prognosis of patients suffering from AF, determining a risk score, and comparing that risk score to a reference to determine the patient’s prognosis and indication of underlying fibrotic scar and arrhythmia recurrence after treatment. Therefore, the instantly claimed invention falls into one of the four statutory categories.
Step 2A Prong 1 – Whether the claim is directed to a judicial exception (i.e. Does the claim recite an abstract idea, law of nature, or natural phenomenon?) - YES
Claims 1 and 2 recite the following steps which fall under mental processes and/or natural correlation:
Claims 1 and 2 disclose methods for predicting the response of/the prognosis of patients suffering from AF by measuring Gal-3 and FABP4 in a sample, determining the AF type, obtaining a risk score from that data, assessing that risk score to a reference to determine whether the patient will not respond to treatment or indicates the presence of underlying fibrotic scar and arrhythmia recurrence. The broadest reasonable interpretation of this step is a method of measuring Gal-3 and FABP4, determining AF type, using the Gal-3 and FABP4 levels and AF type data to determine a risk score, and comparing that risk score to a pre-established reference to determine whether the patient will not respond to treatment or indicative of the presence of underlying fibrotic scar and arrhythmia recurrence.
The “…determining AF type…”, “…processing the concentration level values of Gal-3 and FABP4 and the AF type in order to obtain a risk score…”, and the “…if the risk score obtained in the step b) is higher than a pre-established reference…” all represent mental processes that can be performed in the human mind. While the “…if the risk score obtained in the step b) is higher than a pre-established reference…” does not explicitly recite a “comparison” step, there is inherently one that must be performed to determine if the obtained risk score is higher than the reference. Furthermore, while the specification recites the use of hardware and software to process the concentration level values of Gal-3 and FABP4 and the AF type in order to obtain a risk score ([15]), this processing can easily be performed by the human mind ([30]). Therefore, these “determining”, “processing”, and “comparing” steps represent mental processes.
Claims 1 and 2 recite the use Gal-3 and FABP4 levels and the AF type to indicate whether the patient will not respond to catheter ablation treatment and/or presence of underlying fibrotic scar and arrhythmia recurrence after catheter ablation treatment. The broadest reasonable interpretation of this step is that the combined patient Gal-3 and FABP4 levels and current AF status is being compared to a reference measurement which is then being used to monitor/predict a disease/condition in a subject. Thus, there is a naturally occurring relationship between the Gal-3 and FABP4 levels and a patients underlying cardiac health being observed, which represents a law of nature/natural correlation judicial exception.
Regarding the step of “comparing”, the courts have held similar claims to be abstract mental processes, as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014) which involved claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind. The claims are also similar to that in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011), which involved a claim to “collecting and comparing known information” (both of these court cases are discussed in MPEP 2106.04(a)(2) (II)(A)). The steps of “determining” recited in claims 1 and 2 also constitutes an abstract mental process, involving gathering data from a patient and then making an evaluation or judgment as to what type of AF the patient has. The “comparing” and “determining” steps could be performed in the human mind, or by a human using pen and paper, insofar as it reads on comparing levels and drawing conclusions from this about the health status of a subject.
Furthermore, the “comparing” step can also be regarded as a law of nature, namely, the naturally occurring correlation between the amount of Gal-3 and FABP4 being measured in the patient sample and the presence/risk level of an underlying cardiac condition. Regarding the identification of a correlation between the presence of a biomarker in a bodily sample and disease state the courts have held similar claims to be laws of nature and/or natural phenomena, as in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017) which involved claims to simply instruct a user to apply a natural law, by correlating naturally occurring enzyme levels with disease risk.
Thus, claims 1 and 2 fall into judicial exceptions.
Step 2A: Prong 2 - Does the claim recite additional elements that integrate the judicial exception into a practical application? The Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception.
Claims 1, 2, 3, 5, 6, 8-10, and 14-19 do not recite any additional elements that integrate the judicial exception into a practical application. The additional steps of using a minimally-invasive biological sample obtained from the patient (claims 5, 15, 17) such as plasma, blood or serum (6, 10, 16, 19), are insufficient to integrate the exception into a practical application because the purpose is merely to obtain data.
There are no subsequent steps recited after the “determining”, “processing”, and “comparing” steps that would practically apply the method depending on the results of the measurements, e.g., treatment or other process steps that are performed after the test subject has been diagnosed with an underlying condition/risk.
Step 2B; Whether the additional elements contribute an “inventive concept”. In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP 2106.05.
Briefly, the claims 1, 2, 3, 5, 6, 8-10, and 14-19 do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the following reasons. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional steps of claims 1, 2, 3, 5, 6, 8-10, and 14-19 do not add a meaningful limitation to the instant method as they are directed to data gathering steps that are well-understood, routine and conventional and are used by those of ordinary skill in the art as supported by Clementy (2016). “Serum galectin-3 levels predict recurrences after ablation of atrial fibrillation”. Scientific Reports, 6(1), 34357, (herein referred to as Clementy), in view of Lopez-Canoa et al. (2019). “Plasma FABP4 levels are associated with left atrial fat volume in persistent atrial fibrillation and predict recurrence after catheter ablation”. International Journal of Cardiology, 292, 131-135, (herein referred to as Lopez-Canoa), and Kornej et al. (2015). “The APPLE score: a novel and simple score for the prediction of rhythm outcomes after catheter ablation of atrial fibrillation”. Clinical Research in Cardiology, 104(10), 871-876, (herein referred to as Kornej).
Clementy teaches the in vitro measurement of serum galectin-3 in AF patients (Gal-3) to study its accuracy in predicting AF after ablation (abstract). Clementy teaches patient classification of AF type and the corresponding risk of AF reoccurrence in relation to Gal-3 and LAD levels (page 3, “Type of AF”, paragraphs 1-2). Additionally, Clementy teaches the use of a “Combined Score (0, 1, or 2)” which is calculated as the number of the following risk factors: galectin-3 level ≥ 15 ng/mL; left atrial diameter ≥ 40 mm (Table 3).
Lopez-Canoa teaches the measurement of FABP4 in peripheral and atrial plasma from patients undergoing atrial fibrillation (AF) ablation, and analyzing its association with left atrial adipose tissue (LAAT) volume measured by multi-slice CT, and its predictive value for recurrence after AF ablation (page 132, column 1, 1st full paragraph). Specifically, Lopez-Canoa teaches the in vitro measurement of FABP4 concentration in a plasma sample obtained from a patient (page 132, column 1, 7th full paragraph) and classifying the patients AF type (page 132, column 2, 11th paragraph). Lopez-Canoa also teaches using the concentration level values of FABP4 and the AF type in order to obtain risk levels (page 133, column 2, 1st full paragraph). For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
Kornej teaches a score (APPLE score) for the prediction of rhythm outcomes after catheter ablation of atrial fibrillation (abstract). More specifically, Kornej teaches the development a simple score for the prediction of rhythm outcome following catheter ablation, and validating it in an external cohort (abstract). Kornej teaches that in the external validation cohort, patients with APPLE score of 0, 1, 2, and ≥3 had AF recurrence rates of 46, 57, 76, and 72 %, respectively, implying that a higher APPLE score acts as an indication that the patient will not respond to catheter ablation treatment (page 874, column 1, 3rd full paragraph).
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to a law of nature and abstract idea without significantly more. For additional guidance, applicant is directed generally to MPEP § 2106.
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, 3, 5, 6, and 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Clementy (2016). “Serum galectin-3 levels predict recurrences after ablation of atrial fibrillation”. Scientific Reports, 6(1), 34357, (herein referred to as Clementy), in view of Lopez-Canoa et al. (2019). “Plasma FABP4 levels are associated with left atrial fat volume in persistent atrial fibrillation and predict recurrence after catheter ablation”. International Journal of Cardiology, 292, 131-135, (herein referred to as Lopez-Canoa), and Kornej et al. (2015). “The APPLE score: a novel and simple score for the prediction of rhythm outcomes after catheter ablation of atrial fibrillation”. Clinical Research in Cardiology, 104(10), 871-876, (Kornej), as evidenced by Dretzke (2020). “Predicting recurrent atrial fibrillation after catheter ablation: a systematic review of prognostic models”. EP Europace, 22(5), 748-760, (herein referred to as Dretzke).
Regarding claim 1, Clementy teaches the in vitro measurement of serum galectin-3 (Gal-3) to study its accuracy in predicting AF after ablation (abstract). Clementy teaches that Gal-3 has been suspected of playing a role in promoting atrium fibrosis in patients with AF, and that Gal-3 levels are significantly higher in patients with Ps-AF and have also been correlated with structural LA remodeling (page 1, 2nd paragraph). Clementy teaches that during the early stage of the AF ablation procedure, a blood sample was collected from the patients peripherally through the femoral vein sheath, and patients were followed for 12 months after the procedure (page 2, “Galectin-3”, 1st paragraph; page 2, “Follow-up”, 2nd paragraph). In addition, Clementy teaches performing trans-thoracic echocardiography and cardiac magnetic resonance imaging or CT-scans before ablation to assess left ventricular function and LA diameter (LAD) and volume (page 1, “Methods”, 1st paragraph). Clementy teaches the measurement of serum Gal-3 concentration via immunoassay (page 2, “Galectin-3”, 2nd paragraph), and patient classification of AF type and the corresponding risk of AF reoccurrence in relation to Gal-3 and LAD levels (page 3, “Type of AF”, paragraphs 1-2). Additionally, Clementy teaches the use of a “Combined Score (0, 1, or 2)” which is calculated as the number of the following risk factors: galectin-3 level ≥ 15 ng/mL; left atrial diameter ≥ 40 mm (Table 3). Patients with a score of 2 were at a high risk of AF reoccurance within 1 year following ablation (Table 4). Clementy recites that an LAD ≥ 40 millimeters and a Gal-3 level ≥ 15 ng/mL were found to be accurate independent risk factors of AF recurrence at 1 year, and that combining these two markers further improved accuracy (page 2, “Predictive Factors”).
However, Clementy does not specifically teach measuring the concentration of FABP4 in a patient sample, processing the concentration level values of Gal-3 and FABP4 and the AF type in order to obtain a risk score, and if the risk score is higher than a pre-established reference, it acts as an indication that the patient will not respond to catheter ablation treatment.
Lopez-Canoa teaches the measurement of FABP4 in peripheral and atrial plasma from patients undergoing atrial fibrillation (AF) ablation, and analyzing its association with left atrial adipose tissue (LAAT) volume measured by multi-slice CT, and its predictive value for recurrence after AF ablation (page 132, column 1, 1st full paragraph). Specifically, Lopez-Canoa teaches the in vitro measurement of FABP4 concentration in a plasma sample obtained from a patient (page 132, column 1, 7th full paragraph) and classifying the patients AF type (page 132, column 2, 11th paragraph). Lopez-Canoa also teaches using the concentration level values of FABP4 and the AF type in order to obtain risk levels (page 133, column 2, 1st full paragraph). Lopez-Canoa teaches that both atrial and peripheral FABP4 levels were able to discriminate those patients with persistent AF at a higher risk of recurrence after catheter ablation (page 134, column 1, 1st paragraph).
Kornej teaches a score (APPLE score) for the prediction of rhythm outcomes after catheter ablation of atrial fibrillation (abstract). More specifically, Kornej teaches the development a simple score for the prediction of rhythm outcome following catheter ablation, and comparing it with the CHADS2 and CHA2DS2-VASc scores, and validating it in an external cohort (abstract). The recited APPLE score is constructed by: [one point for age >65 years, AF type, impaired eGFR (<60 ml/min/1.73 m2), left atrial diameter ≥43 mm, left ventricular ejection fraction <50 %, range from 0 to 5] (page 1, column 2, 2nd full paragraph). Kornej teaches that compared to patients with an APPLE score of 0, the risk (OR) for AF recurrences was 1.5 (95 % CI 0.8–3.0, p = 0.185), 3.7 (95 % CI 1.8–7.9, p = 0.001) and 3.0 (95 % CI 1.4–6.8, p = 0.006) for APPLE scores 1, 2, or ≥3, respectively (page 874, column 1, 3rd full paragraph). In the external validation cohort, patients with APPLE score of 0, 1, 2, and ≥3 had AF recurrence rates of 46, 57, 76, and 72 %, respectively, implying that a higher APPLE score acts as an indication that the patient will not respond to catheter ablation treatment (page 874, column 1, 3rd full 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 predicting AF after ablation taught by Clementy to also measure FABP4, as disclosed by Lopez-Canoa, and include it in the risk score along with AF type because the art demonstrates that both Gal-3 and FABP4 are known to be accurate predictors of AF recurrence after ablation. Additionally, Clementy and Kornej demonstrate that having a score that contains multiple variables with value for predicting AF after ablation can improve the predictive power, and Dretzke demonstrates that many such scores/models already exist. It also would have been obvious to compare the risk score to a pre-established reference, as disclosed by Kornej, and use it as an indication that the patient will not respond to catheter ablation treatment when the risk score is higher, as such comparisons between patient data and standard references are routine in the art, and are made when using many risk score AF prognostic models as further evidenced by Dretzke.
A skilled artisan would have been motivated to make this modification in order to create a prognostic model with greater specificity, sensitivity, and/or predictive value to create an individualized risk estimate, which allows physicians and patients to make a more informed decision with regards to catheter ablation treatment and weigh the potential risks and benefits along with the chance of reoccurrence. A person of ordinary skill would have had a reasonable expectation of success in making these modifications because the art demonstrates that: both Gal-3 and FABP4 can be measured using commercially available kits, Gal-3 and FABP4 can act as predictors of whether a patient will not respond to catheter ablation treatment, risk scores that incorporate AF type and known predictors are commonly used in prognostic models of AF reoccurrence after ablation that are used in clinical settings, and those models compare patients levels against a reference level.
Regarding claims 3 and 8, Lopez-Canoa teaches that the method is carried out in persistent AF patients in which a catheter ablation is indicated for treatment (abstract).
Regarding claims 5, 6, 9, and 10 Lopez-Canoa teaches that patients peripheral blood samples were obtained from an ante-cubital vein using an 18-G butterfly cannula (page 132, column 1, 6th full paragraph).
Claims 2, and 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over Clementy, Lopez-Canoa, Kornej, and Dretzke in view of Liu et al. (2020). “Role of sST2 in predicting recurrence of atrial fibrillation after radiofrequency catheter ablation”. Pacing and Clinical Electrophysiology, 43(11), 1235-1241, (herein referred to as Liu).
Regarding claim 2, Clementy, Lopez-Canoa, Kornej, and Dretzke recites nearly all the limitations of claim as discussed above, but does not recite that a bad prognosis indicates the presence of underlying fibrotic scar after catheter ablation treatment.
Liu teaches the examination of the role of sST2 in predicting recurrence of AF after radiofrequency catheter ablation (RFCA) and the relationship between sST2 and abnormalities (defined as low-voltage zones and/or scars) during left atrial endocardial mapping (page 1236, column 1, 1st paragraph; page 1236, column 2, 3rd paragraph). Kiu teaches that many studies have shown that recurrence rate after AF ablation was significantly related with atrial fibrosis extent (page 1328, column 2, 1st full paragraph). Kiu also teaches that sST2 is a profibrotic marker which may account for AF risk and progression, and previous data has shown that sST2 level could predict the recurrence of AF in paroxysmal AF patients undergone cryoballoon ablation (page 1236, column 1, 1st paragraph). Additionally, Liu teaches that sST2 concentrations were measured in patient plasma samples by ELISA using a commercially available kit (page 1236, column 2, 1st paragraph). Finally, Liu teaches that sST2 level was associated with new abnormalities during endocardial mapping and recurrence of AF after ablation (abstract; page 1238, 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 for the prognosis of patients suffering from AF after ablation using a risk score in comparison to a pre-established reference taught by Clementy, Lopez-Canoa, Kornej, and Dretzke, to use the higher risk score to indicate the presence of underlying fibrotic scar and arrhythmia recurrence after catheter ablation treatment, as taught by Liu, as a matter of simple substitution within inventions in the same field. Like sST2, Gal-3 is a known profibrotic marker, and including FABP4, all 3 markers are demonstrated by the art to be predictive of AF reoccurrence after catheter ablation, and are able to be measured using commercially available kits. Furthermore, the art teaches that in AF patients, Gal-3 is associated with structural left atrium remodeling which is often at least partially due to fibrotic scarring.
A skilled artisan would have been motivated to make this modification in order to have the ability to risk stratify the chances of AF recurrence due to atrial matrix structural changes versus recurrence due to pulmonary vein reconnection, which would allow physicians and patients to make a more informed decision with regards to catheter ablation treatment and weigh the potential risks and benefits along with the chance of reoccurrence. A person of ordinary skill would have had a reasonable expectation of success in making these modifications because the art demonstrates that: both Gal-3 and FABP4 can be measured using commercially available kits, and Gal-3 and FABP4 can act as predictors of arrythmia recurrence after AF ablation which is significantly related with atrial fibrosis extent.
Regarding claims 14 and 17, Lopez-Canoa teaches that the method is carried out in persistent AF patients in which a catheter ablation is indicated for treatment (abstract).
Regarding claims 15, 16, 18, and 19 Lopez-Canoa teaches that patients peripheral blood samples were obtained from an ante-cubital vein using an 18-G butterfly cannula, and biomarker concentrations were measured in plasma (page 132, column 1, 6th full paragraph; page 132, column 1, 7th full paragraph).
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Clementy, Lopez-Canoa, Kornej, and Dretzke in view of Zuk et al. (U.S. Patent No. 4208479).
While Clementy, Lopez-Canoa, Kornej, and Dretzke makes obvious the method of claims 1, 3, 5, 6, and 8-10 as discussed above, they do not recite all the reagents together in a kit.
However, Zuk et al. teaches the convenience and accuracy enhancement associated with combining all necessary reagents for an assay together in a kit (column 22, lines 20-68).
Therefore, it would have been obvious to one of ordinary skill in the art to assemble together the reagents (reagents or tools for collecting a sample from patients, reagents or tools for measuring the concentration level of Gal-3 and FABP4, and means, reagents or tools for determining the AF type) in the form of a kit, in order to create a reagent kit for a measuring the concentration level of Gal-3 and FABP4, and for determining the AF type using a sample collected from a patient. A skilled artisan would have had a reasonable expectation of success in assembling the reagents of the patented claims into kits as taught by Zuk because kits are well known as being convenience and economical.
Conclusion
For all the reasons discussed above, claims 1-3, 5, 6, and 8-12, and 14-19 are rejected and therefore no claims are allowed.
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/ALEXANDER J. HOFFMAN/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 June 4, 2026
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