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
Claim 10 has been canceled by Applicant’s amendment filed 05/04/2026. Claim 1 has been amended. Claims 1-9 are pending and examined herein.
Priority
This application, filed 07/25/2023, is a 371 of PCT/IB2022/050708, filed 01/27/2022, and claims benefit of ITALIAN REPUBLIC IT102021000002306 filed on 02/03/2021. This priority is acknowledged and the claims examined herein are treated as having an effective filing date of 02/03/2021.
Information Disclosure Statement
The Information Disclosure Statement filed 07/25/2023 is acknowledged and has been considered.
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 1-7 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 “A process to perform an in vitro diagnosis of the antiphospholipid antibody syndrome (APS) comprising the steps of: a) having available one or more isolated biological samples of the subject to be diagnosed; and b) diagnosing APS syndrome in said subject by contacting said one or more isolated biological samples with carbamylated β2-glycoprotein I, and detecting binding between antibodies against carbamylated β2 glycoprotein and said carbamylated β2-glycoprotein I in said one or more isolated biological samples.”. The steps are judicial exceptions because they are merely observing naturally occurring correlations (laws of nature) and/or mental process grouping of abstract ideas.
This judicial exception is not integrated into a practical application because there is no practical application recited in the claims such as performing 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 instantly claimed invention is directed to a process of diagnosing antiphospholipid antibody syndrome in vitro by measuring antibodies directed towards carbamylated β2-glycoprotein I in a biological sample. 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
Claim 1 recites the following steps which fall under the law of nature and/or mental process grouping of abstract ideas:
Claim 1 discloses a process of diagnosing antiphospholipid antibody syndrome in vitro by measuring binding between antibodies against carbamylated β2-glycoprotein I and β2-glycoprotein I in a biological sample from a subject being diagnosed. The claim process comprises detecting binding between antibodies directed towards carbamylated β2-glycoprotein I in biological sample (claim 1) that can be serum (claim 6), made by post-translation carbamylation (claim 2), and quantifying them (claim 3).
The broadest reasonable interpretation of this step is diagnosing a subject with antiphospholipid antibody syndrome if any amount of antibodies against carbamylated β2-glycoprotein I are detected in the biological samples. This limitation recites a law of nature which is a judicial exception, because it is merely observing the correlation between a naturally occurring biomarker (carbamylated β2-glycoprotein I) and its relationship to a disease/disease state (antiphospholipid antibody syndrome).
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.
The step of “diagnosing” also constitutes an abstract mental process, involving assessing the comparison of expression levels of the biomarker in a test sample, and then making an evaluation or judgment as to whether the test subject has a particular disease. The “diagnosing” step 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.
Thus, claim 1 falls into a judicial exception.
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 1-7 do not recite any additional element that integrate the exception into a practical application of the exception. The additional steps of quantifying the antibodies directed towards the carbamylated β2-glycoprotein I (claim 3), using ELISA assay, chemiluminescence assay, or particle-based multi-analytical technologies (claims 4-5), choosing serum, plasma, urine, synovial fluid, cerebrospinal fluid, saliva, or isolated serum as the biological sample (claims 6-7) are insufficient to integrate the exception into a practical application because the purpose is merely to obtain data to observe a naturally occurring correlation.
As in In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989), such activity involving performing clinical tests on individuals constitutes mere data gathering, and does not go beyond insignificant extra-solution activity. See MPEP §§ MPEP 2106.04(d)(I) and 2106.05(g).
There are no subsequent steps recited after the “diagnosing” step 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 a disease.
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 1-7 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 identifying the antibodies directed towards the β2-glycoprotein I made by post-translation carbamylation (claims 2-3), quantifying them using ELISA assay, chemiluminescence assay, or particle-based multi-analytical technologies (claims 4-5), choosing serum, plasma, urine, synovial fluid, cerebrospinal fluid, saliva, or isolated serum as the biological sample (claims 6-7) do not add a meaningful limitation to the instant method as they would have been routinely used by those of ordinary skill in the art as supported by over Alessandri et al. (2017). “Anti-mutated citrullinated vimentin antibodies in antiphospholipid syndrome: diagnostic value and relationship with clinical features”. Immunologic research, 65(2), 524-531. (referred to herein as Alessandri), in view of Ioannou et al. (2011). “Novel assays of thrombogenic pathogenicity in the antiphospholipid syndrome based on the detection of molecular oxidative modification of the major autoantigen β2‐glycoprotein I”. Arthritis & Rheumatism, 63(9), 2774-2782. (referred to herein as Ioannou), Massaro et al. (2018). Anti-carbamylated protein antibodies in systemic lupus erythematosus patients with articular involvement. Lupus, 27(1), 105-111. (referred to herein as Massaro), and Arvieux et al. (1993). “Platelet activating properties of murine monoclonal antibodies to β2-glycoprotein I”. Thrombosis and haemostasis, 70(08), 336-341. (referred to herein as Arvieux).
Alessandri teaches the quantification of antibodies against post-translationally modified (citrullinated) vimentin anti-β2‐glycoprotein I antibodies to act as a diagnostic biomarker of antiphospholipid antibody syndrome (abstract).
Ioannou teaches the ability to identify patients with antiphospholipid antibody syndrome by measuring the presence of antibodies directed towards post-translationally modified (oxidized) β2‐glycoprotein I in serum samples using ELISA assay (abstract).
Massaro teaches the quantification of antibodies against post-translationally carbamylated autoantibodies to act as a diagnostic marker of autoimmune disease (abstract).
Arvieux teaches the measurement of murine monoclonal antibodies against human carbamylated β2‐glycoprotein I (abstract).
See a detailed discussion of what these references teach in the prior art rejections below.
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).
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.
Amended 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 6, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Alessandri et al. (2017). “Anti-mutated citrullinated vimentin antibodies in antiphospholipid syndrome: diagnostic value and relationship with clinical features”. Immunologic research, 65(2), 524-531. (referred to herein as Alessandri), in view of Ioannou et al. (2011). “Novel assays of thrombogenic pathogenicity in the antiphospholipid syndrome based on the detection of molecular oxidative modification of the major autoantigen β2‐glycoprotein I”. Arthritis & Rheumatism, 63(9), 2774-2782. (referred to herein as Ioannou), Massaro et al. (2018). Anti-carbamylated protein antibodies in systemic lupus erythematosus patients with articular involvement. Lupus, 27(1), 105-111. (referred to herein as Massaro), and Arvieux et al. (1993). “Platelet activating properties of murine monoclonal antibodies to β2-glycoprotein I”. Thrombosis and haemostasis, 70(08), 336-341. (referred to herein as Arvieux), as evidenced by Conti et al. (2014). “The mosaic of “seronegative” antiphospholipid syndrome”. Journal of immunology research, 2014(1), 389601. (referred to herein as Conti).
Regarding claims 1-4, 6, and 7, Alessandri teaches the quantification of antibodies against post-translationally modified citrullinated vimentin (MCV) and other peptides to act as a diagnostic biomarker of antiphospholipid antibody syndrome (abstract). More specifically, Alessandri teaches that to detect anti-MCV, anti-vimentin, anti-vimentin/cardiolipin, anti-CCP2 antibodies, and anti-β2‐glycoprotein I antibodies, commercial or homemade enzyme-linked immunosorbent assays (ELISA) were performed (abstract; page 526, column 2, 3rd full paragraph). Alessandri also teaches that 79.7% of patients with APS tested positive for anti-β2‐glycoprotein I antibodies (Table 2). Alessandri teaches that autoantibodies were measured via ELISA by incubating polystyrene plates overnight at 4 °C with the corresponding protein for the antibody of interest in the wells (page 526, column 1, 3rd full paragraph). Alessandri also teaches that after washing three times with PBS-T, the wells were incubated for 1h at room temperature with 100 μL of patient sera, diluted 1:100 in the blocking buffer (page 526, column 2, 1st paragraph). Alessandri teaches that binding detection was done using horseradish peroxidase conjugated antibodies, either goat anti-human IgG or rabbit anti-goat IgG diluted with 1% BSA in PBS; the plates were washed three times with PBS-T and the bound peroxidase was revealed with 100 μL/well of O phenylendiamine dihydrochloride; color reaction was stopped with 0.2 M H2SO4 for 5 min; absorbance was measured at 492 nminamicroplate reader (page 526, column 2, 1st paragraph). Alessandri teaches that antiphospholipid antibody syndrome can be the primary disease or secondary to other autoimmune diseases such as systemic lupus erythematosus (page 525, column 2, paragraph 2). Alessandri also teaches that anti-citrullinated vimentin antibodies can be useful for the diagnosis of other autoimmune diseases such as rheumatoid arthritis, and patients that have combination cases of systemic lupus erythematosus and rheumatoid arthritis (page 529, column 1, 3rd full paragraph). Alessandri teaches that the detection of additional autoantibodies may contribute to clinical assessment of APS patients (abstract).
However, Alessandri does not teach that the β2‐glycoprotein I is carbamylated, made by post-translation modification by carbamylation.
Ioannou teaches that levels of both total and oxidized β2‐glycoprotein I were found to be elevated in patients with APS as compared to disease and healthy control groups (page 2775, column 2, 1st paragraph). Ioannou also teaches that quantification of posttranslational modifications of β2‐glycoprotein I in conjunction with standard laboratory tests for APS may offer the potential to more accurately predict the risk of occurrence of a thrombotic event in the setting of APS (abstract). Ioannou teaches a sandwich ELISA for quantifying total β2‐glycoprotein I levels within serum/plasma samples was based on a previously published method, with modifications (page 2776, column 2, 3rd paragraph). Ioannou also teaches that the β2‐glycoprotein I is made by the post-translation modification of β2‐glycoprotein I (abstract). Ioannou also teaches the quantification of antibodies directed towards the post-translationally modified (oxidized) β2‐glycoprotein I using ELISA assay (page 2777, column 1, second full paragraph and paragraph 3). Ioannou also teaches the selection of isolated serum as the biological sample to be used assay (page 2776, column 2, paragraph 3).
Massaro discloses the quantification of antibodies against another post-translationally carbamylated autoantibodies to act as a diagnostic marker of another prothrombic autoimmune disease (systemic lupus erythematosus) (abstract). Massaro teaches that anti-carbamylated proteins antibodies are found in higher levels in other autoimmune disease (psoriatic arthritis) patients compared to healthy subjects (page 110, column 1, first full paragraph). Massaro also teaches that anti-carbamylated proteins antibodies are found in the serum of rheumatoid arthritis patients before the onset of symptoms, and in some seronegative patients (page 105, column 2, second full paragraph).
Arvieux teaches the use of carbamylated β2‐glycoprotein I for use in platelet aggregation assays. Arvieux teaches the measurement of murine monoclonal antibodies against human carbamylated β2‐glycoprotein I using radioimmunoassay (abstract).
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 taught by Alessandri in view of Ioannou, Massaro, and Arvieux to measure antibodies directed toward carbamylated β2‐glycoprotein I, as it would be “obvious to try”. β2‐glycoprotein I is known in the art to be the major autoantigen involved in antiphospholipid antibody syndrome (Ioannou, abstract), and as the art demonstrates that other post-translationally carbamylated autoantibodies have been measured for use as diagnostic markers of prothrombic autoimmune diseases with success, including antiphospholipid antibody syndrome, carbamylated β2‐glycoprotein I would be an obvious choice of an additional biomarker to measure by one of ordinary skill in the art.
A skilled artisan would have been motivated to make this modification because some patients present with clinical symptoms of antiphospholipid antibody syndrome but are negative for the laboratory tests for APS, as evidenced by Conti (abstract). Therefore, it would be invaluable to identify other antigenic targets for antiphospholipid antibodies that are present in seronegative APS patients for diagnostic and treatment purposes, as well as for risk stratification for APS symptoms like thrombosis (Ioannou, abstract). A person of ordinary skill would have had a reasonable expectation of success in performing an in vitro diagnosis of APS by identifying antibodies against carbamylated β2‐glycoprotein I because quantifying antibodies against human carbamylated β2‐glycoprotein I has previously been taught by Arvieux and the quantification of post-translationally carbamylated autoantibodies is known in the art as demonstrated by Massaro.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Alessandri in view of Ioannou, Massaro, and Arvieux as applied to claims 1-4, 6, and 7 above, and further in view of Sciascia et al. (2020). “Evaluation of novel assays for the detection of autoantibodies in antiphospholipid syndrome”. Autoimmunity reviews, 19(10), 102641. (referred to herein as Sciascia).
The teachings of Alessandri in view of Ioannou, Massaro, and Arvieux are incorporated herein.
Regarding claim 5, Alessandri in view of Ioannou, Massaro, and Arvieux teaches the identification of antibodies toward carbamylated β2‐glycoprotein I, but does not teach the use of particle-based multi-analytical technologies.
Regarding claim 5, Sciascia teaches the use of particle-based multi-analyte technology (PMAT) to perform antiphospholipid antibody panel testing (that includes β2‐glycoprotein I) in order to discover new biomarkers to better diagnose patients suspected for APS (abstract). Sciascia also teaches that the current testing criteria for APS is insufficient to identify all patients with APS when they exhibit clinical symptoms, and also that the number of different antibodies associated with APS is constantly increasing (page 1, column 1, paragraph 2).
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 taught by Alessandri in view of Ioannou, Massaro, and Arvieux to use particle-based multi-analyte technology, as disclosed in Sciascia, to identify carbamylated β2‐glycoprotein I because it allows for simultaneous detection of autoantibodies and other proteins which saves time. Such simultaneous detection allows for the shift to a “personalized medicine approach” which could allow for “…disease prediction and prevention, early and accurate diagnosis, and effective and timely treatment…” (Sciascia, page 3, column 2, paragraph 1). The skilled artisan would have been motivated to use PMAT because it allows for extra criteria testing for antiphospholipid antibodies which could aid diagnosis of seronegative patients. A person of ordinary skill would have had a reasonable expectation of success in making this modification because similar to the methods of Alessandri, Ioannou, Massaro, Sciascia teaches the use of patient serum and ELISA for the detection of autoantibodies in antiphospholipid syndrome/autoimmune disease.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Alessandri in view of Ioannou, Massaro, and Arvieux in view of Zuk et al. (U.S. Patent No. 4208479).
In addition to the details of Alessandri, Ioannou, Massaro, and Arvieux discussed above, Massaro also teaches the method of measurement of antibodies where a carbamylated autoantibody is absorbed on the solid phase, a secondary antibody is tagged with alkaline phosphatase, and the substrate of the enzyme is paranitrophenyl-phosphate (page 106, column 2, 5th full paragraph).
Furthermore, 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 (carbamylated β2‐glycoprotein, alkaline phosphatase-conjugated antibody, paranitrophenyl-phosphate, etc.) in the form of a kit, in order to create an assay kit for identifying and quantifying carbamylated β2‐glycoprotein I as described by Alessandri, Ioannou, Massaro, and Arvieux. A skilled artisan would have been motivated to combine all necessary reagents together in a kit, because kits are well known as being convenient and economical. A person of ordinary skill would have had a reasonable expectation of success in in assembling the reagents of the patented claims into kits as taught by Zuk because the creation and use of kits is a practice that is well-understood, routine and conventional in the field.
Response to Arguments
Applicant's arguments filed 05/04/2026 have been fully considered but they are not persuasive except to the extent expressly indicated below.
Applicant’s arguments on page 5 with respect to the rejection of claim 10 under 35 U.S.C. 112(b) as being indefinite have been fully considered and are persuasive. Claim 10 has been canceled by Applicant. Accordingly, the rejection of claim 10 under 35 U.S.C. 112(b) has been withdrawn.
Applicant’s arguments on page 5 with respect to the rejection of claim 10 under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends have been fully considered and are persuasive. Claim 10 has been canceled by Applicant. Accordingly, the rejection of claim 10 under 35 U.S.C. 112(d) has been withdrawn.
Applicant’s arguments on page 7 with respect to the rejection of claim 10 under 35 U.S.C. 103 over Ioannou in view of Massaro, Alessandri, and Arvieux have been fully considered and are persuasive. Claim 10 has been canceled by Applicant. Accordingly, the rejection of claim 10 under 35 U.S.C. 103 has been withdrawn.
Applicant’s arguments on pages 5-7 with respect to the rejection of claims 1-7 under 35 U.S.C. 101 for being directed to a judicial exception and a law of nature without significantly more have been fully considered but are not persuasive. The rejections under 35 U.S.C. 101 are maintained and have been updated, where appropriate, in view of Applicant's claim amendments. Any modification to the statement of the rejection, including reliance on additional prior art, is necessitated by Applicant's amendments to the claims and is made to address the newly added or clarified claim limitations.
Presently amended claim 1 recites “A process to perform an in vitro diagnosis of the antiphospholipid antibody syndrome (APS) comprising the steps of: a) having available one or more isolated biological samples of the subject to be diagnosed; and b) diagnosing APS syndrome in said subject by contacting said one or more isolated biological samples with carbamylated β2-glycoprotein I, and detecting binding between antibodies against carbamylated β2 glycoprotein and said carbamylated β2-glycoprotein I in said one or more isolated biological samples.”
Applicant argues on page 6 that these steps do not recite or describe any recognized exception. Applicant merely recites “See May Collaborative Svcs v. Prometeus Labs., 566 U.S., 132, S. Ct 1289, 1297 (2012) (recited steps of administering a drug to a patient and determining the resultant level of 6-thioguanine in the patient "are not themselves natural laws")”. This argument is not persuasive. An important distinction is that in the cited case there was a treatment step, as disclosed by Applicant, which is lacking in the instant application. Furthermore, with regards to Mayo Collaborative Servs. v. Prometheus Labs., 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012), the courts decided that a correlation that is the consequence of how a certain compound is metabolized by the body is identified as an example of laws of nature or natural phenomena. Furthermore, in Mayo, the Supreme Court concluded that a step of determining thiopurine metabolite levels in patients’ blood did not amount to significantly more than the recited laws of nature, because this additional element simply instructed doctors to apply the laws by measuring the metabolites in any way the doctors (or medical laboratories) chose to use. 566 U.S. at 79, 101 USPQ2d at 1968. Therefore, it is maintained that the claim recites a law of nature, and the Applicant’s assertion that “analysis of this claim ends with eligibility at Step 2A, the Step 2B analysis does not need to be performed” is not persuasive.
Applicant also argues on pages 6-7 that “Although nature-based product limitations are recited in the claim (e.g., the one or more isolated biological samples and the carbamylated ß2-glycoprotein I), analysis of the claim as a whole indicates that the claim is focused on a process of detecting whether antibodies against carbamylated ß2-glycoprotein I is present in the biological samples and is not focuses on the products per se. Thus, there is no need to perform the markedly different characteristics analysis on the recited nature-based product limitations”.
This argument is not persuasive. Applicant asserts that the claim as a whole is focused on the process and not on the products per se, however, as discussed above, the rejection to the claim does not rely on a nature-based product alone. As discussed above, the claim is directed to a judicial exception which is the naturally-occurring correlation between subjects suffering from APS and the presence/amount of antibodies against carbamylated β2 glycoprotein I. The presence of antibodies against carbamylated β2 glycoprotein I is inherent to the disease. As outlined in the rejection, the claim also does not recite any additional elements that integrate the exception into a practical application of the exception, such as a specific treatment step or any other steps which amount to significantly more. Additionally, the additional elements in the claim do not contribute an “inventive concept”, as they are obvious over Alessandri in view of Ioannou, Massaro, and Arvieux as outlined in the above rejection.
Additionally, Applicant failed to address the part of the rejection asserting that the “diagnosing” step is also a judicial exception (abstract mental process) that 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.
Therefore, claims 1-7 are not drawn to eligible subject matter as they are directed to a law of nature and abstract idea without significantly more and the rejection has been updated and is maintained. Applicant has amended claim 1 which has necessitated a modification to the rejection.
Applicant’s arguments on pages 7-9 with respect to the rejection of claims 1-4, 6, and 7 under 35 U.S.C. 103 over Ioannou in view of Massaro, Alessandri, and Arvieux have been fully considered but are not persuasive. Applicant argues that “…for the foregoing reasons, the combination of the cited references would not have rendered obvious the presently claimed invention to one skilled in the art. First, Massaro, Alessandri and Arvieux either describe antibodies different from the antibody claimed or they describe different diseases. Ioannou is completely silent with regard to the critical finding of Applicants, that is that is the presence of the carbamylated ß2-glycoprotein I that allows for the diagnosis of APS even in patients which cannot be diagnosed with the methods already present in the prior art. Thus, one skilled in the art, by combining and modifying the cited references as suggested by the Examiner would be forced to undergo undue experimentation with a limited, if any, reasonable expectation of success”.
Applicant’s reply fails to address the combined teaching of the applied references and instead only argues that each reference individually does not teach all of the claim limitations, as discussed in MPEP § 2145(IV). One cannot show nonobviousness by attacking reference individually where the rejections are based on combinations of references. All of the limitations of the claim are disclosed in either Ioannou, Massaro, Alessandri, and Arvieux, and the combination of the references renders the claimed invention obvious. Alessandri is relied upon for the teaching that antibodies against post-translationally modified (citrullinated) proteins as well as anti-β2‐glycoprotein I antibodies can act as a diagnostic biomarker of antiphospholipid antibody syndrome. Thus, the only deficiency of Alessandri with regards to the claim is the antibodies were not against carbamylated β2‐glycoprotein I specifically. Massaro and Ioannou make obvious why one of ordinary skill would then modify Alessandri to measure antibodies towards carbamylated β2‐glycoprotein I instead. Massaro provides the teaching that antibodies directed towards post-translationally carbamylated proteins can act as a diagnostic marker of prothrombic autoimmune disease. Ioannou is relied upon for the teaching that the ability to identify patients with antiphospholipid antibody syndrome by measuring the presence of post-translationally modified (oxidized) β2‐glycoprotein I in biological samples. Lastly, Arvieux teaches the measurement of murine monoclonal antibodies against human carbamylated β2‐glycoprotein.
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 taught by Alessandri in view of Ioannou, Massaro, and Arvieux to measure antibodies directed toward carbamylated β2‐glycoprotein I, as it would be “obvious to try”. β2‐glycoprotein I is known in the art to be the major autoantigen involved in antiphospholipid antibody syndrome (Ioannou, abstract), and as the art demonstrates that other post-translationally carbamylated autoantibodies have been measured for use as diagnostic markers of prothrombic autoimmune diseases with success, including antiphospholipid antibody syndrome, carbamylated β2‐glycoprotein I would be an obvious choice of an additional biomarker to measure by one of ordinary skill in the art.
A skilled artisan would have been motivated to make this modification because some patients present with clinical symptoms of antiphospholipid antibody syndrome but are negative for the laboratory tests for APS, as evidenced by Conti (abstract). Therefore, it would be invaluable to identify other antigenic targets for antiphospholipid antibodies that are present in seronegative APS patients for diagnostic and treatment purposes, as well as for risk stratification for APS symptoms like thrombosis (Ioannou, abstract). A person of ordinary skill would have had a reasonable expectation of success in making these modifications because quantifying antibodies against human carbamylated β2‐glycoprotein I has previously been taught by Arvieux and the quantification of post-translationally carbamylated autoantibodies in biological samples is frequently performed in the art as taught by Ioannou, Massaro, and Alessandri. Therefore, the Applicant’s assertion that one skilled in the art, by combining and modifying the cited references as suggested by the Examiner would be forced to undergo undue experimentation with a limited, if any, reasonable expectation of success, is not considered persuasive.
Therefore, applicant’s arguments are not persuasive and the rejection of claims 1-4, 6 and 7 as obvious over Ioannou, Massaro, Alessandri, and Arvieux is maintained. Applicant has amended claim 1 which has necessitated a modification to the rejection.
Applicant’s arguments on pages 8-9 with respect to the rejection of claim 5 under 35 U.S.C. 103 over Ioannou in view of Massaro, Alessandri, and Arvieux have been fully considered but are not persuasive. Applicant argues that claim 1 is patentable over the combination of the teachings of Ioannou, Massaro, Alessandri, Arvieux and Sciascia, and because claim 5 depends from independent claim 1, it is patentable as well. As discussed above, the combination of Ioannou, Massaro, Alessandri, and Arvieux does make obvious the methods of claim 1. Additionally, Applicant provides no arguments against the teachings of Sciascia. Accordingly, the rejection against claim 5 is maintained. Applicant has amended claim 1 which has necessitated a modification to the rejection.
Applicant’s arguments on page 9 with respect to the rejection of claims 8 and 9 under 35 U.S.C. 103 over Ioannou, Massaro, Alessandri, and Arvieux in view of Zuk et al. have been fully considered but are not persuasive.
Applicant argues that “Zuk does not contributes to render obvious the subject matter of
claims 8 and 9. Specifically, Zuk only describes the convenience and accuracy enhancement
associated with combining all necessary reagents for an assay together in a kit. However, as discussed above, Ioannou, Massaro, Alessandri and Arvieux either describe the presence of carbamylated ß2-glycoprotein I associated with other type of diseases, or do not describe carbamylated ß2-glycoprotein I at all. It should be reminded that is the presence of the post-translational carbamylated form of the ß2-glycoprotein I that allows the diagnosis of the APS”.
As discussed above, the combination of Ioannou, Massaro, Alessandri, and Arvieux does make obvious the process of performing an in vitro diagnosis of APS by measuring carbamylated β2‐glycoprotein I. A skilled artisan would have been motivated to combine all necessary reagents together in a kit, because kits are well known as being convenient and economical. A person of ordinary skill would have had a reasonable expectation of success in in assembling the reagents of the patented claims into kits as taught by Zuk because the creation and use of kits is a practice that is well-understood, routine and conventional in the field. Accordingly, the rejection against claims 8 and 9 are maintained. Applicant has amended claim 1 which has necessitated a modification to the rejection.
Conclusion
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.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached at (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALEXANDER J. HOFFMAN/ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 July 27, 2026
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