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
Claims 1-10 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 03/22/2024 are acknowledged and have been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 10 is 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 10 recites “…wherein said antibodies directed against the carbamylated β2-glycoprotein I are biomarkers of the antiphospholipid antibody syndrome (APS)” as a further limitation of claim 1. However, the recited language of “biomarker” is indefinite because it is unclear in what way that identification of the antibodies will be used to link them to antiphospholipid antibody syndrome, which could be done in several ways. For example, the mere presence of the antibodies could indicate antiphospholipid antibody syndrome, or perhaps once the levels reach a certain threshold. It is also unclear how use as a “biomarker” is different from diagnosing via identification of the same antibodies as in the limitations of claim 1.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 10 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 10 depends upon claim 1 which 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) identifying, within said one or more samples according to step a), the presence of antibodies directed towards carbamylated β2-glycoprotein I”.
This limitation of claim 1 establishes the use of carbamylated β2-glycoprotein I as a biomarker of the antiphospholipid antibody syndrome. Therefore, claim 10 fails to further limit the subject matter of claim 1, as it merely recites this already existing limitation taught in claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 and 10 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 of performing an in vitro diagnosis of the antiphospholipid antibody syndrome (APS)…” by measuring “presence of antibodies directed towards carbamylated β2-glycoprotein I”. The steps are judicial exceptions because they are merely observing naturally occurring correlations (laws of nature). This judicial exception is 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 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 mathematical concepts grouping of abstract ideas:
Claim 1 discloses a process of diagnosing antiphospholipid antibody syndrome in vitro by measuring antibodies directed towards carbamylated β2-glycoprotein I in a biological sample from a subject being diagnosed. The claim process comprises identifying 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), quantifying them (claim 3), and using them as a biomarker of antiphospholipid antibody syndrome (claim 10).
The broadest reasonable interpretation of this step is diagnosing a subject with antiphospholipid antibody syndrome if any amount of carbamylated β2-glycoprotein I antibodies 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 and 10 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), or identifying antibodies directed against the carbamylated P2-glycoprotein I (claim 10) 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 “determining” 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 and 10 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), or identifying antibodies directed against the carbamylated P2-glycoprotein I to use as a biomarker (claim 10), 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 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) in view of 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), 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)
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).
Alessandri teaches the quantification of antibodies against post-translationally modified (citrullinated) vimentin to act as a diagnostic biomarker of antiphospholipid antibody syndrome (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.
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 1-7 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over 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) in view of 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), 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 and 10, 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 biological samples (abstract).
Regarding claim 2, Ioannou teaches that the β2‐glycoprotein I is made by the post-translation modification of β2‐glycoprotein I (abstract).
Regarding claims 3 and 4, 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).
Regarding claims 6 and 7, Ioannou teaches the selection of isolated serum as the biological sample to be used assay (page 2776, column 2, paragraph 3).
Ioannou does not teach that the β2‐glycoprotein I is carbamylated, made by post-translation modification by carbamylation.
However, 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).
Furthermore, Alessandri teaches the quantification of antibodies against post-translationally modified (citrullinated) vimentin to act as a diagnostic biomarker of antiphospholipid antibody syndrome (abstract). 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).
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 Ioannou in view of Massaro, Alessandri, and Arvieux to measure antibodies directed toward carbamylated β2‐glycoprotein I, because β2‐glycoprotein I is the major autoantigen in antiphospholipid antibody syndrome (Ioannou, abstract), and other post-translationally carbamylated autoantibodies have been measured for use as potential diagnostic markers of autoimmune diseases, including antiphospholipid antibody syndrome.
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 frequently performed in the art.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Ioannou in view of Massaro, Alessandri, and Arvieux as applied to claims 1-6 and 10 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 Ioannou in view of Massaro, Alessandri, and Arvieux are incorporated herein.
Regarding claim 5, Ioannou in view of Massaro, Alessandri, 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 Ioannou in view of Massaro, Alessandri, 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 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.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Ioannou, Massaro, Alessandri, and Arvieux in view of Zuk et al. (U.S. Patent No. 4208479).
In addition to the details of Ioannou, Massaro, Alessandri, 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 Ioannou, Massaro, Alessandri, and Arvieux. 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 1-10 are rejected and therefore no claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER JOSEPH HOFFMAN whose telephone number is (571)272-9080. The examiner can normally be reached PTA 7:30-5:00 M-F.
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/ALEXANDER J. HOFFMAN/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 March 2, 2026