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 .
Status of the Claims
The amended claim set received 02 October 2025 has been entered into the application.
Claims 1 and 19 are amended.
Claims 6, 8-9, and 11-18 are previously cancelled.
Claim(s) 1-5, 7, 10, and 19-20 are pending.
Priority
Acknowledgment is made of applicant’s claim for priority to PCT/EP2019/073180 filed 30 August 2019 which claims further priority to U.S Patent Application 16/118,572 filed 31 August 2018.
The instant application is a continuation of PCT/EP2019/073180.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12 September 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
It is noted the copy of NPL Citation No. 2 is not legible. Therefore, a legible copy of the NPL is requested.
Claim Rejections - 35 USC § 101
The instant rejection is maintained for reason for record in the Office Action mailed 29 July 2025 and modified in view of the amendments filed 02 October 2025. It is noted the amendments received 02 October 2025 necessitated new ground(s) of rejection.
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 1-5, 7, 10, and 19-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Step I - Process, Machine, Manufacture or Composition
Claims 1-5, 7, and 10 are drawn towards a method for determining a prognostic index (PI), so a process.
Claims 19-20 are drawn to a computer-readable storage medium comprising instructions for determining a prognostic index, so a manufacture.
2A Prong I - Identification of an Abstract Idea
Claim 1 is drawn towards a method for determining a prognostic index (PI) while claim 19 is drawn to a computer-readable storage medium comprising instructions for determining a prognostic index. Claims 1 and 19 encompass similar limitations. Claims 1 and 19 are examined similarly.
Claims 1 and 19 recite:
a) determine at least the following parameters: i) extranodal disease status indicative of a presence or an absence of an extranodal disease; ii) Ann Arbor stage; iii) the level of thymidine kinase 1 (TK-1), iv) age; and v) ECOG (Eastern Cooperative Oncology Group) performance status
This step can be performed in the human mind by following instructions to determine parameters and is therefore an abstract idea. Moreover, the step also reads on mathematical concepts or relationships such as mathematical variables.
Claims 1 and 19 recite
includes variable heavy chain associated with a first defined amino acid sequence and a variable light chain associated with a second defined amino acid sequence
This step describes the antibody or antibody fragment that binds to the TK-1 as including a variable heavy chain associated with a first defined amino acid sequence and a variable light chain associated with a second defined amino acid sequence which reads on the mental process of knowing the sequences of the binding antibody.
This step can be performed in the human mind by observing and evaluating an operation to bind an antibody or an antigen fragment to an epitope of an analyte associated with TK-1 to determine the level of TK-1 that includes a variable heavy chain associated with a first defined amino acid sequence and a variable light chain associated with a second defined amino acid sequence and is therefore an abstract idea.
Claims 1 and 19 recite:
wherein if an extranodal disease is absent, the value is 0 points and if an extranodal disease is present, the value is 1 point,
This step can be performed in the human mind by observing and evaluating information about whether extranodal disease is absent or present to value the extranodal disease as 1 if disease is present or as 0 if disease if absent and is therefore an abstract idea.
wherein if the Ann Arbor stage is I or II the value is 0 points and if the Ann Arbor stage is III or IV the value is 1 point
This step can be performed in the human mind by observing and evaluating information about whether to value Ann Arbor stages I or II as 0 and observing and evaluating information about whether to value Ann Arbor stages III or IV as 1 and is therefore an abstract idea.
wherein if the level of the thymidine kinase 1 is less than or equal to a predetermined cut-off value the value is 0 points and wherein if the level of the thymidine kinase 1 is above the predetermined cut-off value the value is at least 1 point.
This step can be performed in the human mind by observing and evaluating information to determine whether the level of the thymidine kinase 1 is less than or equal to a predetermined cut-off value to value the TK-1 levels as 0 and is therefore an abstract idea. This step can be performed in the human mind by observing and evaluating information to determine whether the level of the thymidine kinase 1 is above a predetermined cut-off value to value the TK-1 levels as 1 and is therefore an abstract idea. This step encompasses the mathematical concepts of using equalities and inequalities for evaluating if the level of the thymidine kinase 1 is above or below a threshold and therefore reads on abstract ideas.
wherein if the age is below a second predetermined cut-off value, the value is 0 points and if the age is above the second predetermined cut-off value, the value is 1 point
This step can be performed in the human mind by observing and evaluating information to determine whether age is below a second predetermined threshold to value age as 0 and is therefore an abstract idea. This step can be performed in the human mind by observing and evaluating information to determine whether age is above a second predetermined threshold to value age as 1 and is therefore an abstract idea. This step encompasses the mathematical concepts of using equalities and inequalities for evaluating if age is above or below a threshold and therefore reads on abstract ideas.
wherein, in case the ECOG performance status is 1 or below, the value is 0 points; wherein, in case the ECOG performance status is 2 or above, the value is 1 point,
This step can be performed in the human mind by observing and evaluating information to determine whether the ECOG performance status is 1 or below to value the status as 1 and observing and evaluating information to determine whether the ECOG performance status is 2 or above to value the status as 2 and is therefore an abstract idea. This step encompasses the mathematical concepts of using equalities and inequalities for evaluating if the ECOG performance status is 1 or below or if the ECOG performance status is 2 or above to value the ECOG performance status as 0 or 1 and therefore reads on abstract ideas.
b) sum up the points for i), ii), iii), iv) and v), thereby in determining the PI.
This step can be performed in the human mind by organizing data (i.e., i), ii), iii), iv), and v)) to determine a prognostic index (PI) and is therefore an abstract idea. This step encompassing summing values (i.e., i), ii), iii), iv), and v)) to determine a PI which encompasses the mathematical concept of summation/adding and therefore reads on an abstract idea.
Claims 2-5, 7, and 10 and 20 are further drawn to limitations that describe the abstract idea performed in claims 1 and 19 and are therefore also abstract ideas.
2A Prong II - Consideration of Practical Application
Claims 1 and 19 do not recite any additional elements and therefore cannot integrate the recited judicial exception into a practical application. Here, in the instant case, the claims merely set forth a method of data analysis for determining a prognostic value. As such, practicing the claims merely results in a summation of values (i.e., i) extranodal disease status indicative of a presence or an absence of an extranodal disease; ii) Ann Arbor stage; iii) the level of thymidine kinase 1 (TK-1), iv) age; and v) ECOG (Eastern Cooperative Oncology Group) performance status) to determine a prognostic index (PI). Such a result only produces information and does not provide for a practical application in the physical realm of things and acts, i.e., the claims do not utilize the data generated by the judicial exception to affect any type of change. See MPEP 2106.04(a)(2)(A)(iv). Therefore, the determined parameters for determining the PI and the abstract ideas do not construct a practical application such as treating a subject, transformation of matter, or improving upon an existing technology.
This recited additional element of extracting a sample of claims 1 and 19 do not integrate the recited judicial exception into a practical application because performing clinical/laboratory procedures for extracting samples that can subsequently be used as a source for biomarkers is deemed an extra-solution activity of data gathering. See MPEP 2106.05(d)(II)(i) and 2106.05(g).
This recited additional element of using samples of claims 1 and 19 does not integrate the recited judicial exception into a practical application because using sample(s) (i.e., blood, urine, serum, plasma) as a source of TK-1 biomarkers is deemed an extra-solution activity. See MPEP 2106.05(g).
This recited additional element of using variable heavy and light chain amino acid sequences of claims 1 and 19 does not integrate the recited judicial exception into a practical application because using antibodies and antibody fragment using different variable heavy and light chain for binding biomarkers is deemed an extra-solution activity. See MPEP 2106.05(g).
This recited additional element of using antibody binding of claim 1 does not integrate the recited judicial exception into a practical application because using antibodies or antibody fragments to determine thymidine kinase-1 level in a sample is deemed an extra-solution activity. See MPEP 2106.05(g).
The recited additional element of using computer processes, components, and equipment of claims 19-20 does not integrate the recited judicial exception into a practical application because using non-transitory computer readable storage medium to store and process abstract ideas is tangential to the claimed method. See MPEP 2106.05(b) and 2106.05(d).
This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
an additional element effects a transformation or reduction of a particular article to a different state or thing; and
an additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
2B Analysis - Consideration of Additional Elements and Significantly More
The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea.
This recited additional element of using TK-1 biomarkers of claims 1 and 19 does not add more than the recited judicial exception because using TK-1 biomarkers from a sample that are subsequently analyzed by the abstract idea is deemed a well-known and conventional extra-solution activity. See MPEP 2106.05(g).
This recited additional element of extracting a sample of claims 1 and 19 does not add more than the recited judicial exception because performing clinical/laboratory procedures for extracting samples that can subsequently be used as a source of biomarkers is deemed a well-known and conventional extra-solution activity. See MPEP 2106.05(d)(II)(i) and 2106.05(g).
This recited additional element of using samples of claims 1 and 19 does not add more than the recited judicial exception because using sample(s) (i.e., blood, urine, serum, plasma) and extracting and quantifying TK-1 biomarkers from the samples as subsequent data input is deemed a well-known and conventional extra-solution activity. See MPEP 2106.05(g).
This recited additional element of using antibody binding of claims 1 and 19 does not add more than the recited judicial exception because using antibodies or antibody fragments to determine thymidine kinase-1 level is deemed well-known and conventional. See MPEP 2106.05(g). To provide evidence of conventionality, Gronowitz teaches a kit for determining Thymidine Kinase activity [title]. Gronowitz teaches using the enzyme-labelled affinity conjugate is an antibody labelled with alkaline phosphatase or horseradish peroxidase [claim 6] (Cited in the Office Action mailed 29 July 2025) (US9376707 Date 28 June 2016). To provide further evidence of conventionality, Bonechi et al. (Bonechi) teach using The DiviTum assay, used in the present study to assess TK1 activity, measures both forms of TK [page16393 left col]. Bonechi teaches TK1 activity was determined by a refined ELISA based method, the DiviTum assay [page 16393 right col TK1 activity] (Cited in the Office Action mailed 29 July 2025) (Oncotarget. 2018 Mar 27;9(23):16389–16399). To provide further evidence of conventionality of using sample (i.e., blood, serum, plasma) and in vitro antibody methods for determining TK-1 levels, Eriksson et al. (Eriksson) discloses using antibody and antibody fragments against TK-1 to determine levels of TK-1 [Eriksson, claims 1-4] (US Patent: 6,083,707; US Patent Date: 04 July 2000). To provide further evidence of conventionality, Oehrvik et al. (Oehrvik) discloses in vitro methods using a sample and in vitro assaying of the sample to determine levels or TK-1 [Oehrvik, claims 15-16] (US Patent Pub: US 2006/0035295; Patent Pub Date: 16 Feb 2006).
The recited additional element of using computer processes, components, and equipment of claims 19-20 does not add more than the recited judicial exception because using non-transitory computer readable storage medium to store and process abstract ideas is deemed conventional and well-known. See MPEP 2106.05(b) and 2106.05(d).
In conclusion and when viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Response to Arguments
Applicant’s arguments, filed 02 October 2025, have been fully considered but the rejection is maintained. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments filed 02 October 2025.
The Applicant points to the USPTO 2019 Eligibility guidance for guidance. [remarks, page 8]. The Applicant states “ the claims do not recite a mental process when they do not contain limitations that can practically be performed in the human mind." (See October Update, p. 7). The Applicant states “that is the case with at least those limitations of independent claim 1. The features of independent claim 1 simply cannot practically be performed in the human mind, which would be readily appreciated to any person of ordinary skill in the art.” [remarks, page 8-9].
In response and as noted in Step 2A Prong I of the 101 analysis above, the claims encompass determining parameters (i.e., TK-1 levels, Ann Arbor Stage, ECOG) and observing, comparing, and judging whether the extranodal disease, Ann Arbor stage, ECOG, and TK-1 are above or less than a predetermined threshold which reads on abstract ideas and summing up points to determine a prognostic index (PI) related to a diffuse large B-cell lymphoma (DLBCL) in a patient (i.e., mathematical concept) which reads on abstract ideas/mathematical concepts. Therefore, the claims encompass abstract ideas.
The Applicant describes Step 2A Prong II of the 101 analyses [remarks, page 9]. The Applicant points to pages 9-10 of Non-Final Office Action mailed 29 July 2025 for guidance [remarks, page 9-10]. The Applicant states “the claim was amended to recite a specific operation that are performed to determine levels of TK-1 of the patient.” The Applicant points to amend claim 1 and the specification paragraphs [0057] and [0094] for further clarification. [remarks, page 10-11].
In response, the claims 1 and 19 are drawn to gathering and analyzing information (i.e., i) extranodal disease status indicative of a presence or an absence of an extranodal disease, ii) Ann Arbor stage, iii) the level of thymidine kinase 1 (TK-1), iv) age, and v) ECOG (Eastern Cooperative Oncology Group) performance status) using conventional techniques (i.e., using samples and in vitro binding) and displaying the results (i.e., summed PI). See MPEP 2106.05(a)(II)(iii). Here, claims 1 and 19 do not encompass any additionally elements that integrate the recited judicial exception into a practical application. Additionally, using standard laboratory techniques (i.e., in vitro antibody binding) to detect enzyme levels or levels of biomarkers in a bodily sample (i.e., blood, serum, plasma) is merely performing clinical to test to obtain input for an equation (i.e., summing up the points for i), ii), iii), iv) and v) for determining the PI) which is an extra-solution activity that does not integrate the recited judicial exception into a practical application. See MPEP 2106.05(a)(II)(iii), 2106.05d(II)(ii), and 2106. 2106.05(g). Here, the PI is not integrated with any additional elements such as to construct a practical application or improvement an existing technology. Therefore, the specific operations performed to determine TK-1 does not integrate the recited judicial exception into a practical application.
The Applicant states “the extraction and the binding” processes are indicative of a physical transformation and is integral to the determining step. The Applicant points to the MPEP 2106.04(d) for guidance. The Applicant states at least one those amended features of claim 1 integrates the claim into a practical application. The Applicant states “As such, the claims represent more than a drafting effort to monopolize a judicial exception and instead are indicative of integration into a practical application.” [remarks, page 11-12].
In response, the extracting and binding steps encompass additional elements that do not integrate the judicial exception (i.e.., determined PI) into a practical application. Here, for example, extracting samples encompasses gathering a source (i.e., blood, plasma, serum) of biomarkers (i.e., TK-1) while binding antibodies to TK-1 proteins (i.e., clinical/laboratory testing) encompasses quantifying biomarkers from a sample to obtain input (i.e., mathematical variables) for an equation (i.e., summing values to determine a prognostic index (PI)) [MPEP 2106.05(d)(II)(i) and 2106.05(g)(i) and (iv)] which does not construct a practical application of the judicial exception.
The Applicant discusses the Step 2B of the 101 analyses. The Applicant states “that each of the amended claims recites significantly more than the abstract idea, regardless of the characterization of the claims as an abstract idea.” The Applicant points to the Berkheimer memo for further guidance. The Applicant states “that when considering the recitations of claim 1 as a whole rather than as a set of disconnected parts, the subject matter of claim is novel and nonobvious over the prior art of record and includes one or more "additional features" that are not well-understood, routine, or conventional. As such, the Applicant respectfully submits that the additional elements of the claims, considered alone or in combination, constitute significantly more than an abstract idea.” [remarks, pages 11-12].
In response and with respect to Step 2B of the 101 analyses, the claimed additional elements and step are well-understood and conventional. They encompassed additional elements of extracting TK-1 biomarkers, using samples, using antibody binding, and using computer processes, components, and equipment which are well-known and conventional. For example, collecting a sample to provide a source of TK-1 biomarkers that can be quantified using antibody binding assays to obtain TK-1 levels. Furthermore, the computer elements are merely used to process and store the instructions for determining the PI which is merely tangential to the claimed steps. Importantly, regarding Step 2B of the 101 analyses, the MPEP 2106.05(I) states an inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016). ... Evaluating additional elements to determine whether they amount to an inventive concept requires considering them both individually and in combination to ensure that they amount to significantly more than the judicial exception itself.” Therefore, because the claims do not encompass further additional elements or a combination of additional elements that can be analyzed for an “inventive concept”, the claims, under Step 2B, do not provide significantly more than the abstract idea.
Here, the claims are drawn to mere gathering and analyzing information (i.e., i) extranodal disease status indicative of a presence or an absence of an extranodal disease; ii) Ann Arbor stage; iii) the level of thymidine kinase 1 (TK-1), iv) age; and v) ECOG (Eastern Cooperative Oncology Group) performance status) using conventional clinical/laboratory techniques for detecting enzymes/biomarkers in a bodily sample (i.e., in vitro antibody assays) and displaying the results (i.e., determining a prognostic index (PI)). See MPEP 2106.05(a)(II)(iii). Furthermore, the claims are drawn to determining levels of biomarkers in blood by any means (i.e., in vitro antibody assays) and obtaining levels of biomarker (i.e., TK-1) by performing clinical tests (i.e., in vitro binding assays) to obtain TK-1 biomarker level input that is subsequently summed with other data to determine a prognostic index (PI) which are extra-solution activities that do not provide an inventive concept. See MPEP 2106.05(d)(II)(i).
In conclusion and when viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 103
The instant rejection is maintained for reason for record in the Office Action mailed 29 July 2025 and modified in view of the amendments filed 02 October 2025. It is noted the amendments received 02 October 2025 necessitated new ground(s) of rejection.
The rejection of claim(s) 1-3, 7, 10, and 19 under 35 U.S.C. 103 as being unpatentable over Zhou et al. (Cited in the IDS filed 11 March 2021 Citation No. 37; Cited in the Office Action mailed 19 December 2024) in view of Kim et al. (Cited in the Office Action mailed 19 December 2024) in the Office Action mailed 29 July 2025 is withdrawn in view of the amendments received 02 October 2025.
The rejection of claims 4-5 under 35 U.S.C. 103 as being unpatentable over Zhou in view of Kim, as applied to claims 1-3, 7, 10, and 19, and in further view of Suzuki et al. (Cited in the Office Action mailed 19 December 2024; Leukemia & lymphoma, 2013-11, Vol.54 (11), p.2412-2417) in the Office Action mailed 29 July 2025 is withdrawn in view of the amendments received 02 October 2025.
The rejection of claim 20 under 35 U.S.C. 103 as being unpatentable over Zhou in view of Kim, as applied to claims 1-3, 7, 10, and 19, and in further view of MDApp (“https://www.mdcalc.com/calc/3936/international-prognostic-index-diffuse-large-b-cell-lymphoma-ipi-r-ipi#when-to-use; Cited in the Office Action mailed 19 December 2024) in the Office Action mailed 29 July 2025 is withdrawn in view of the amendments received 02 October 2025.
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.
Claim(s) 1-3, 7, 10, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (Cited in the IDS filed 11 March 2021 Citation No. 37; Cited in the Office Action mailed 19 December 2024) in view of Kim et al. (Cited in the Office Action mailed 19 December 2024) in view of Ericksson et al. (WO 2015/094106: Pub Date: 25 June 2015).
Claims 1 and 19 recite a) determine at least the following parameters: i) extranodal disease status indicative of a presence or an absence of an extranodal disease; ii) Ann Arbor stage; iii) the level of thymidine kinase 1 (TK-1), iv) age; and v) ECOG (Eastern Cooperative Oncology Group) performance status.
Claim 1 recites wherein determining the level of thymidine kinase 1 (TK-1) includes (claim 1) and/or is based on (claim 19) extraction of a sample that includes one or more of blood, serum, plasma, synovial fluid, urine, saliva, lymphatic fluid, tissue extracts, cartilage, bone, synovium, or connective tissue from the patient and an operation to bind, in vitro, an antibody or an antigen fragment to an epitope of an analyte associated with TK-1 that includes a variable heavy chain associated with a first defined amino acid sequence and a variable light chain associated with a second defined amino acid sequence
Claims 1 and 19 recite wherein if an extranodal disease is absent, the value is 0 points and if an extranodal disease is present, the value is 1 point, wherein if the Ann Arbor stage is I or II the value is 0 points and if the Ann Arbor stage is III or IV the value is 1 point.
Claims 1 and 19 recite wherein if the level of the thymidine kinase 1 is less than or equal to a predetermined cut- off value the value is 0 points and wherein if the level of the thymidine kinase 1 is above the predetermined cut-off value the value is at least 1 point.
Claims 1 and 19 recite wherein if the age is below a second predetermined cut-off value, the value is 0 points and if the age is above the second predetermined cut-off value, the value is 1 point.
Claims 1 and 19 recite wherein, in case the ECOG performance status is 1 or below, the value is 0 points; wherein, in case the ECOG performance status is 2 or above, the value is 1 point.
Claims 1 and 19 recite b) sum up the points for i), ii), iii), iv) and v), thereby in determining the PI.
Zhou et al. (Zhou) teach an enhanced international prognostic index (NCCN-IPI) for patients with diffuse large B-cell lymphoma [title]. Zhou teaches the IPI is made up of five clinical characteristics including age, lactate dehydrogenase (LDH), number of extranodal sites, Ann Arbor stage, and Eastern Cooperative Oncology Group (ECOG) performance [page 837], as in claims 1 and 19 determine at least the following parameters: i) extranodal disease status indicative of a presence or an absence of an extranodal disease; ii) Ann Arbor stage, iv) age, and v) ECOG (Eastern Cooperative Oncology Group) performance status.
Zhou teaches diffuse large B-cell lymphoma [abstract]. With respect to extracting a sample (i.e., blood, serum, plasma), it is known in the art that diffuse large B-cell lymphoma (DLBCL) is a common cancer of B lymphocytes (infection-fighting white blood cells) that forms large tumors in lymph nodes and other organs like the spleen, bone marrow, or liver. Therefore, it would be obvious to extract TK-1 biomarkers from samples such as blood, plasma, bone, or serum for determining TK-1 levels in a subject with diffuse large B-cell lymphoma (DLBCL).
Zhou teaches age is a score using 0-1 [839 table 2], as in claim 7.
Zhou does not teach claims 1 and 19 iii) determining the level of thymidine kinase 1 (TK-1). Zhou does not teach claims 1 and 19 wherein determining the level of thymidine kinase 1 (TK-1) includes (claim 1) and/or is based on (claim 19) an operation to bind, in vitro, an antibody or an antigen fragment to an epitope of an analyte associated with TK-1 that includes a variable heavy chain associated with a first defined amino acid sequence and a variable light chain associated with a second defined amino acid sequence
Kim et al. (Kim) also teach an IPI score that uses age, performance status, clinical stage, number of extranodal lesions, and LDH [page 2 second paragraph].
Kim teaches measuring TK1 concentrations using chemiluminescence immune assay [page 3 2. Measurement method], as in claims 1 and 19 iii) the level of thymidine kinase 1 (TK-1).
Kim teach measuring TK1 concentrations using chemiluminescence immune assay [page 3 2. Measurement method]. Kim teaches setting a reference range for TK1 [page 4 1. Reference range], as in claim 1 determining the level of thymidine kinase 1 (TK-1) includes binding an antibody or an antigen fragment to an epitope of an analyte associated with TK-1, and claim 19 the determination of the level of thymidine kinase 1 (TK-1) is based on an operation to bind an antibody or an antigen fragment to an epitope of an analyte associated with TK-1.
Ericksson et al. (Ericksson) also discloses an in vitro antibody/antibody fragment binding method for determining TK-1 levels in human blood serum [Ericksson, claim 1]. Ericksson discloses different monoclonal antibody or fragment variable heavy chains sequences that are known and therefore read on a first defined amino acid sequence and variable light chain sequences that could be utilized as a second defined amino acid sequence [Ericksson, claims 2 and 5-7]
With respect to claims 1 and 19 wherein if an extranodal disease is absent, the value is 0 points and if an extranodal disease is present, the value is 1 point, the claimed limitation is obvious because Zhou teaches extranodal disease sites is greater than 1 [page 839 right col]. Zhou teaches extranodal disease with a score of 1 [page 839 table 3]. Here, it would be obvious for the extranodal disease to be valued at 0 if the disease is absent, and the extranodal disease to be valued at 1 if the disease is present.
With respect to claims 1 and 19 wherein if the Ann Arbor stage is I or II the value is 0 points and if the Ann Arbor stage is III or IV the value is 1 point, the claimed limitation is obvious because Zhou teaches Ann Arbor stage II-IV being scored as 1. Here, it would be obvious to cluster the stages separately (i.e., Ann Arbor stages I-II and III-IV) in order to value the Ann Arbor stages I-II as 0 because Zhou teaches valuing Ann Arbor stages III-IV as 1.
With respect to claims 1 and 19 wherein if the level of the thymidine kinase 1 is less than or equal to a predetermined cut- off value the value is 0 points and wherein if the level of the thymidine kinase 1 is above the predetermined cut-off value the value is at least 1 point, the claimed limitation is obvious because Zhou teaches LDH-R using a predetermined cutoff of less than or equal to 1, greater than 1-3, and greater than 3 which is scored from 0-2 [page 839 table 3]. Here, it would be obvious that the TK-1 concentrations would be scored similar to LDH-R as the TK-1 would merely be substituted for the LDH-R or LDH. Therefore, it would be obvious to score TK-1 similarly as LDH.
With respect to claims 1 and 19 wherein if the age is below a second predetermined cut-off value, the value is 0 points and if the age is above the second predetermined cut-off value, the value is 1 point, the claimed limitations are obvious because Zhou teaches using different predetermined cut-offs for age ranging from 0-3 depending upon whether the age of the patient is less than or equal to 40 or greater than 75 years old [page 839 table 3].
With respect to claims 1 and 19 wherein, in case the ECOG performance status is 1 or below, the value is 0 points; wherein, in case the ECOG performance status is 2 or above, the value is 1 point, the claimed limitation is obvious because Zhou teaches scoring an ECOG of greater than or equal 2 as 1. Here, it would be obvious to score an ECOG of less than 2 as 0.
With respect to claims 1 and 19 b) sum up the points for i), ii), iii), iv) and v), thereby in determining the PI, the claimed limitation is obvious because it is known in the art and common knowledge that the total score of the international prognostic index (IPI) is utilized to categorize patients in risk groups such as: low, low-intermediate, high-intermediate, or high risk. See MPEP 2144.03.
With respect to claims 2-3, the claims are obvious because Kim teaches a healthy controls and B-cell lymphoma patients with TK-1 level 4 to 20 times the mean [page 4 fig 1] and because Zhou teaches LDH level using scores between 0-3. Here, it would be obvious to score the TK-1 values based on increased values compared to healthy individuals. It would be further obvious to use the scoring system of 0-3 of Zhou for scoring TK1 levels based on the TK1 levels of the healthy controls and B-cell Lymphoma patients of Kim [page 4 figure 1].
With respect to claim 10, the claim is obvious because Zhou teaches when age is less than or equal to 40 it is scored as a 0, when age is 41-60 it scored as 1, when age is 61-75 it is score as 2 and when age it greater than 75 it is score as 3. The claim is further obvious because Zhou teaches the ECOG PS is greater than and equal to 2 and is scored as 1 [839 table 2]. Here, it would be obvious to score the ECOG as 0 if the ECOG is less than 2.
It would be obvious to one of ordinary skill in the art by the effective filing date of the claimed invention to modify Zhou in view of Kim because Kim teaches measuring and analyzing TK-1 concentrations and correlating TK-1 concentrations to characteristics encompassed with the international prognostic index (IPI) such as age, clinical stage, extranodal lesions, performance status, and LDH. One of ordinary skill in the art would be motivated to combine Zhou in view of Kim because Kim teaches measuring TK-1 concentrations with respect to determining an international prognostic index (IPI). As such, there is a reasonable expectation of success combining Zhou in view of Kim because Kim teaches correlating TK-1 concentrations to characteristics encompassed within the international prognostic index (IPI) such as age, sites of involvement, clinical status, performance status, for example. Here, there is a further reasonable expectation of success to simply substitute the TK-1 concentrations of Kim for the LDH concentrations of Zhou to yield/determine a prognostic index (PI) for patients with diffuse large B-cell lymphoma (DLBCL).
It would be obvious to one of ordinary skill in the art by the effective filing date of the claimed invention to modify Zhou in view of Kim in view of Ericksson because Ericksson discloses using monoclonal anti-TK-1 antibodies for determining levels of TK-1 is serum samples. One of ordinary skill in the art would be motivated to combine Zhou in view of Kim in view of Ericksson because Ericksson discloses determining levels of TK-1 using anti-TK-1 antibodies using multiple variable heavy chains and variable light chains for targeting/binding TK-1 [Ericksson, claims 2 and 5-7]. Thus, there would be a reasonable expectation of success to combine the monoclonal antibodies and fragments containing the variable heavy and light chains of Ericksson with the in vitro methods of Ericksson and the chemiluminescent in vitro assay of Kim to obtain/determine TK-1 levels in order to sum/combine “i) extranodal disease status, ii) Ann Arbor stage, iii) the level of thymidine kinase I (TK-1), iv) age, and v) ECOG (Eastern Cooperative Oncology Group) performance status” into prognostic index (PI). Therefore, combining the monoclonal antibodies and fragment containing the different variable heavy and light chain regions of Ericksson with the chemiluminescence assay of Kim would yield a predictable method for determining TK-1 levels that can be subsequently utilized for determining a prognostic index (PI) for a diffuse large B-cell lymphoma (DLBCL) patient.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou in view of Kim in view of Ericksson, as applied to claims 1-3, 7, 10, and 19, and in further view of Suzuki et al. (Cited in the Office Action mailed 19 December 2024; Leukemia & lymphoma, 2013-11, Vol.54 (11), p.2412-2417).
Zhou in view of Kim in view of Ericksson teach claims 1-3, 7, 10, and 19.
Zhou in view of Kim in view of Ericksson teach a method for obtaining parameters (i.e., “i) extranodal disease status, ii) Ann Arbor stage, iii) the level of thymidine kinase I (TK-1), iv) age, and v) ECOG (Eastern Cooperative Oncology Group) performance status) for determining a prognostic index (PI) for a diffuse large B-cell lymphoma (DLBCL) patient.
Zhou in view of Kim in view of Ericksson do not teach claims 4-5.
Suzuki et al. (Suzuki) teach TK activity range from 8-340 which encompasses the TK-1 ranges of 18 U/I to 88 U/I [page 2416 left col], as in claim 4.
With respect to claim 5, the claim is obvious because Suzuki teaches low TK arm of 88 [page 2414 table 1]. Suzuki teaches the cut-offs of TK activity were defined as the median levels of serum TK activity among patients with PTCLs and DLBCL, which were 23 IU/L (range, 8 – 340 IU/L) and 14.0 IU/L (range, 3.0 – 1100 IU/L). Zhou [page 839 Tables 2 and 3] in view of Kim [page 3 table 1 and page 6 table 2] teaches tables summarizing and categorizing parameters using a 0-3 system based on cut-off values of age, LDH, ECOG, Ann Arbor, and extranodal disease, for example.
It would be obvious to one of ordinary skill in the art by the effective filing date of the claimed invention to modify Zhou in view of Kim in view of Ericksson, and in further view of Suzuki because Suzuki teaches thymidine kinase as a well- establish prognostic factor [page 2413 right col statistical analysis]. One of ordinary skill in the art would be motivated to combine Zhou in view of Kim in view of Ericksson, and in further view of Suzuki because Suzuki expands on the methods of Kim by providing thymidine kinase as a prognostic marker for investigating DLBCL using an IPI. One of ordinary skill in the art would expect a reasonable success combining Zhou in view of Kim in view of Ericksson, and in further view of Suzuki because Suzuki teaches a TK-1 threshold/range that encompasses the TK concentrations of the claims [page 2416 left]. Here, combining the TK-1 threshold/range of Suzuki with Zhou in view of Kim in view Ericksson would yield a predictable threshold/range to which TK-1 concentrations could be scored in order to determine a prognostic index (PI) using a summation of different parameters including TK-1.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Zhou in view of Kim in view of Ericksson, as applied to claims 1-3, 7, 10, and 19, and in further view of MDApp (“https://www.mdcalc.com/calc/3936/international-prognostic-index-diffuse-large-b-cell-lymphoma-ipi-r-ipi#when-to-use; Cited in the Office Action mailed 19 December 2024).
Zhou in view of Kim in view of Ericksson teach claims 1-3, 7, 10, and 19.
Zhou in view of Kim in view of Ericksson teach a method for obtaining parameters (i.e., “i) extranodal disease status, ii) Ann Arbor stage, iii) the level of thymidine kinase I (TK-1), iv) age, and v) ECOG (Eastern Cooperative Oncology Group) performance status) for determining a prognostic index (PI) for a diffuse large B-cell lymphoma (DLBCL) patient.
Zhou in view of Kim in view of Ericksson do not teach claim 20 age-related IPI.
MDApp teaches age-adjusted IPI [page 3]. With respect to claim 3, it would be obvious that a PI can be selected from group because MDApp teaches age-adjusted IPI [page 3]. Zhou teaches IPI [page 837 left col]. Zhou teaches an R-IPI [page 837 right col]. Zhou teaches NCCN-IPI [title and page 839 table 2].
It would have been further obvious to one of ordinary skill in the art by the effective filing date of the claimed invention to modify Zhou in view of Kim in view of Ericksson, and in further view of MDApp because the MDApp teaches a general medical application that calculates a lymphoma prognostic score. One of ordinary skill in the art would be motivated to combine Zhou in view of Kim in view of Ericksson, and in further view of MDApp because the MDApp teaches an application that sums age, Ann Arbor stage, elevated serum LDH, ECOG, and extranodal sites to produce a prognostic score. Furthermore, there is a reasonable expectation of success combining Zhou in view of Kim in view of Ericksson, and in further view of MDApp because MDApp teach some of the same parameters for evaluating DLBCL. Furthermore, using and combining the TK-1 concentrations of Kim and Ericksson with the software application of MDApp is merely a combination of known elements that would yield a predictable result of being able to measure DLBCL status using TK-1 levels to determine a prognostic index.
Response to Arguments
Applicant’s arguments, filed 02 October 2025, have been fully considered but the rejection is maintained. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments filed 02 October 2025. Here, Zhou, Kim, Ericksson, Suzuki, and MDapp address the issues raised in the amendments filed 02 October 2025.
Conclusion
Claims 1-5, 7, 10, and 16-18 are rejected.
No claims are allowed.
Finality
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/J.C.P./ Examiner, Art Unit 1687
/Anna Skibinsky/
Primary Examiner, AU 1635