DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Status of the Claims
Claims 37-52 are pending and examined herein.
Priority
This application, 18/563,723, filed 11/22/2023, is a 371 of PCT/CA2022/050849 filed on 05/26/2022, and claims benefit of provisional application 63/202,080 filed on 05/26/2021. This priority is acknowledged and the claims examined herein are treated as having an effective filing date of 05/26/2021.
Information Disclosure Statement
The Information Disclosure Statements filed on 11/22/2023 are acknowledged and have been considered.
Claim Objections
Claim 37 recites the abbreviation “SLE” being used for the first time. The first recitation of an abbreviation should be accompanied with the full term/terminology in the interest of improving clarity of the record.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 37-43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 37 recites “A method for processing or preparing a human biological sample, the method comprising obtaining a biological sample from a human subject having or suspected of having SLE, and quantifying a panel of mitochondrial autoantibodies, the panel comprising mitochondrial autoantibodies specific to one or more mitochondrial autoantigenic polypeptides, wherein said one or more mitochondrial autoantigenic polypeptides is or comprises mitofusin-1 (Mfn-1) or C1qBP.”. While the preamble of the claim recites processing/preparing a human biological sample, it is unclear how this could be done given that the body of the claim does not teach any sample processing/preparing steps, and is therefore indefinite. Rather, the body of the claim teaches the quantification of a panel of mitochondrial autoantibodies, and it is unclear how these steps teach a method of processing/preparing a human biological sample. Furthermore, the specification teaches that sample preparation/processing consists of steps such as mitochondrial isolation, antibody panning, serum pooling, immunoprecipitations, and the corresponding wash/dilution steps (page 23, 5th paragraph; page 24, paragraphs 1-4), which is not embodied by what is recited in the body of the claim.
Appropriate correction is required.
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 37-40, 43-48, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Becker et al. (2019). “Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations”. Scientific reports, 9(1), 4530, (IDS dated 11/22/2023, herein referred to as Becker) in view of Xu et al. (1995). “p32, a platelet autoantigen recognized by an SLE-derived autoantibody that inhibits platelet aggregation”. Journal of autoimmunity, 8(1), 97-119, (herein referred to as Xu), Ghebrehiwet et al. (2019). “The C1q receptors: focus on gC1qR/p33 (C1qBP, p32, HABP-1) 1”. In Seminars in Immunology (Vol. 45, p. 101338). Academic Press, (IDS dated 11/22/2023, herein referred to as Ghebrehiwet), and Kurien et al. (2006). “Autoantibody determination in the diagnosis of systemic lupus erythematosus”. Scandinavian journal of immunology, 64(3), 227-235, (herein referred to as Kurian).
Regarding claims 37, 40, and 48 Becker teaches novel assays to detect autoantibodies specific to two distinct components of the mitochondrion: the mitochondrial outer membrane and mitochondrial DNA, and that antibodies to these two mitochondrial constituents were increased in both human and murine systemic lupus erythematosus (SLE), compared to controls, and were present at higher levels than in patients with antiphospholipid syndrome or primary biliary cirrhosis (abstract). Becker also teaches that measurements were done on human sera, and blood samples were collected from both SLE and APS patients (page 10, “Study Approval”). Becker also teaches that for SLE patients, anti-dsDNA was measured using the Farr assay and the anti-cardiolipin were measured by ELISA in a clinical laboratory (page 10, “Data from clinical laboratories”). Becker also teaches that evaluation of antibodies to mitochondrial components in SLE may provide novel information on patients, such as their risk for developing nephritis, and if these findings are confirmed in a large prospective cohort of SLE patients, AwMA and AmtDNA may prove useful in predicting disease activity and disease severity, and in stratifying SLE patients (page 9, 4th paragraph – page 10, 1st paragraph). Becker also teaches that the quantification of mitochondrial antibodies may thus open the way to novel directions in autoimmune disease research and may be useful for achieving a better understanding of disease mechanisms (page 10, 1st paragraph).
However, Becker does not teach that the mitochondrial autoantibodies quantified are specific to the mitochondrial autoantigenic polypeptides mitofusin-1 (Mfn-1) or C1qBP.
Xu teaches a surface-labelled poly peptide of 32,000 molecular weight called p32 which is recognized and bound by an SLE-derived human hybridoma antibody (9604) (abstract). Additionally, Xu teaches that that p32 is a subunit of an activation marker that is expressed on the surface of activated platelets and recognized by an additional SLE-derived anti-platelet auto antibody (8E8) (abstract). Xu also teaches that anti-platelet autoantibodies occur in approximately 78% of patients with SLE (page 98, 1st paragraph). Xu teaches that Human hybridoma monoclonal antibodies are ideal tools for characterizing the autoantibodies produced in autoimmune diseases and defining epitopes that are autoimmunogenic in humans (page 98, 2nd paragraph). Xu teaches that 9604 is an SLE-derived anti-platelet auto antibody that immunoprecipitates a surface-labeled polypeptide (p32), reacts with activated but not resting platelets, and dramatically inhibits secondary platelet aggregation (page 113, 1st full paragraph).
Ghebrehiwet teaches that, p32, gC1qR, p33, C1qBP, and HABP1 are all synonymous for the receptor for the globular heads of C1q, and is a ubiquitously expressed, highly conserved, highly acidic and highly charged cellular protein which is found both inside the cell on the surface as well as a secreted protein (page 2, column 2, 2nd full paragraph). Furthermore, Ghebrehiwet also not only teaches that deficiency of C1q is associated with several diseases including SLE, but also that C1q deficiency is postulated to be the major trigger of the disease (page 7, column 2, 1st full paragraph). Ghebrehiwet also teaches that by virtue of its significance in the mitochondria, gC1qR is expected to be present in all tissues of all species (page 6, column 2, 3rd paragraph). Ghebrehiwet teaches that the ubiquitous cellular distribution of gC1qR, together with its mitochondrial, cytoplasmic and cell surface localization as well as secreted forms suggests that it is involved in a diversity of cellular functions both inside and outside the cell (page 4, column 1, 1st paragraph).
Kurien teaches that SLE is an autoimmune disease that is characterized by the presence of autoantibodies, and that diagnosis is difficult as SLE is a great imitator of other diseases (abstract). Kurien teaches that commonly measured autoantibodies in the diagnosis of SLE include antinuclear antibodies and anti-double-stranded DNA antibodies, anti-Sm and anti-RNP antibodies, all of which target nuclear antigens. Furthermore, the measurement of these antibodies for SLE diagnosis either lack sensitivity or don’t correlate with disease severity, making diagnosis of SLE difficult antigens (page 229, column 1, 3rd paragraph; page 230, column 1, 2nd full paragraph; page 231, column 1, 2nd paragraph). Additionally, Kurien teaches that antibodies to C1q, by ELISA, are detected in 90% of SLE patients (page 231, column 2, 1st full paragraph).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantifying mitochondrial autoantibodies specific to mitochondrial autoantigenic polypeptides, as taught by Becker, to quantify mitochondrial autoantibodies to C1qBP/p32, as disclosed by Xu, as it would be “obvious to try”. Becker teaches the base method which is measuring a panel of autoantibodies to peptides present in SLE patients, Xu teaches that C1qBP/p32 is a autoantigenic polypeptide recognized by SLE-derived autoantibodies and is found on platelets, Kurian teaches that antibodies to the complement protein C1q are found in 90% of SLE patients, and Ghebrehiwet teaches that C1qBP/p32 has mitochondrial, cytoplasmic and cell surface localization as well as secreted forms, and is highly conserved and ubiquitously expressed allowing for easy detection. These teachings make the antibodies against C1qBP/p32 an ideal candidate when searching for an additional SLE marker to include in a panel.
A skilled artisan would have been motivated to make these modifications to the method taught by Becker, as it fills a gap in the field of autoantibody panel/diagnosis for SLE. The most commonly measured autoantibodies in the diagnosis of SLE all target nuclear antigens, and either lack sensitivity or don’t correlate with disease severity, making diagnosis of SLE difficult, as taught by Kurian. The method of Becker measures only autoantibodies specific to two distinct components of the mitochondrion. C1qBP/p32 however, has multiple localizations (including the mitochondria) and is ubiquitously expressed, and therefore measuring antibodies that target this antigen in an antibody panel for diagnosing SLE could improve the disease detection sensitivity of panels. Additionally, one would be motivated to measure antibodies against C1qBP/p32 for SLE patient stratification, as Xu teaches that such antibodies inhibited platelet aggregation, and immune thrombocytopenia and thrombosis are common disease manifestations in SLE patients. Becker also teaches that the quantification of mitochondrial antibodies may thus open the way to novel directions in autoimmune disease research and may be useful for achieving a better understanding of disease mechanisms. A person of ordinary skill would have had a reasonable expectation of success in making these modifications because: measurement of antibodies, including antibodies against mitochondrial peptides, is a well-understood, routine, and conventional activity in the art.
Regarding claims 38, 43, and 51, Becker teaches quantifying the panel of mitochondrial autoantibodies using an immunoassay (page 10, “Data from clinical laboratories”; page 12, “Detection of antibodies targeting mitochondrial epitopes by ELISA”).
Regarding claim 39 and 47, Becker teaches the use of serum samples (page 10, “Study Approval”).
Regarding claims 44-46, Becker teaches that for the detection of anti-whole mitochondrial antibodies (AwMA), murine mitochondria were diluted (500 µg/mL) in 50 mM car bonate/bicarbonate buffer, pH 9.6 and 25 µL per well were loaded onto 96-well half-area clear flat bottom polysty rene high-binding microplates (Corning, New York, USA). Plates were coated for 18 h at 4 °C then blocked for 4 h at 37 °C with PBS containing 10% FBS and 0.5% gelatin. After three washes with PBS, sera diluted 1:150 (unless otherwise specified) in PBS-10% FBS-0.3% gelatin were incubated overnight at 4 °C in duplicate. After three washes with PBS, plates were incubated for 1 h at room temperature with alkaline phosphatase-(AP) conjugated goat anti-mouse or anti-human IgG (Sigma-Aldrich) diluted 1:1,000 in PBS-0.4% bovine serum albumin (BSA). Plates were washed thrice with PBS and developed with p-nitrophenol phosphate (p-NPP) for ~30 min at 37 °C and optical densities (OD) were read at 405 nm on a microplate reader. The same protocol was used for the detection of autoantibodies targeting submitochondrial particles by using 25 µL per well of SMP diluted (50 µg/mL) in 50 mM carbonate/bicarbonate buffer, pH 9.6. A similar approach was used for human mitochondria (page 12-13, “Detection of antibodies targeting mitochondrial epitopes by ELISA”).
Claims 41, 42, 49, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Becker in view of Xu, Ghebrehiwet, and Kurian as applied to claims 37-40 and 43 above, and further in view of Dima et al. (2015). “Extended antiphospholipid antibodies screening in systemic lupus erythematosus patients”. Romanian Journal of Internal Medicine, 53(4), 321-328, (herein referred to as Dima).
The teachings of Becker in view of Xu, Ghebrehiwet, and Kurian are incorporated herein.
Regarding claims 41, 42, 49, and 50, Becker in view of Xu, Ghebrehiwet, and Kurian recites all of the limitations of claim 37 and 44 of the application, and Becker additionally recites that anti-whole mitochondria antibodies and anti-mitochondrial DNA antibodies were measured in serum samples collected from APS patients in addition to SLE patients (page 10, “Study approval”; Figs. 3 and 4).
However, Becker in view of Xu, Ghebrehiwet, and Kurian does not teach that the systemic lupus erythematosus (SLE) is accompanied by a secondary syndrome or disorder, or that the secondary syndrome or disorder is antiphospholipid syndrome (APS).
Dima teaches an investigation of the association of antiphospholipid antibodies (APLAs) titers with the presence of secondary APS diagnosis in SLE patients. (abstract). Additionally, Dima teaches that among the APS patients, one third to 45% are secondary to the SLE or have SLE-like disease, and that these data suggest that the occurrence of both APS and SLE might have common determinants (page 1, column 2, 1st paragraph). Dima teaches the collection of blood samples from three defined groups of patients: SLE patients with secondary APS, SLE with history of positive “criteria” APLAs but without APS clinical features, respectively SLE patients without positive APLAs or clinical APS criteria (abstract; page 2, column 2, 1st paragraph). Dima teaches performing an extended APLAs panel was searched in all cases: both IgM and IgG of anticardiolipin antibodies (aCL), anti-β2 glycoprotein I antibodies (aβ2GPI), antiphosphatidylethanolamine antibodies (aPE), antiphosphatidylserine antibodies (aPS), respectively antiprothrombin antibodies (aPT), and that all measurements were performed via ELISA (page 2, column 1, 2nd and 3rd paragraphs). Furthermore, Dima teaches that SLE patients with positive APLAs tend to have early disease onset as well as more severe disease outcomes, and that the patients with SLE alone when compared to those with SLE and secondary APS had higher SLE’s onset age and almost three times longer median SLE’s disease duration, suggesting the development of the APS in the middle of the SLE immune processes (page 4, column 1, 1st full paragraph). Dima also teaches that the presence of SLE itself might play a role in thrombosis development as the risk of APS’s clinical manifestation is greater in SLE with secondary APS than in primary APS (page 325, column 2, 1st full paragraph).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantifying mitochondrial autoantibodies specific to specific to C1qBP in human subjects having or suspected of having SLE, as taught by Becker in view of Xu, Ghebrehiwet, and Kurian, to perform the method in SLE patients that have APS as a secondary syndrome, as disclosed by Dima, because the two diseases have a high level of cooccurrence, and patients with SLE and secondary APS have earlier disease onset as well as more severe disease outcomes compared to those with SLE alone.
A skilled artisan would have been motivated to make these modifications to the method taught by Becker in view of Xu, Ghebrehiwet, and Kurian, because Dima teaches that both APS and SLE might have common determinants, therefore, measuring mitochondrial autoantibodies in patients that suffer from both may provide a better understanding of the risk and disease severity, and allow for improved patient care. A person of ordinary skill would have had a reasonable expectation of success in making these modifications because: measurement of antibodies, including antibodies against mitochondrial peptides, is a well-understood, routine, and conventional activity in the art, and Becker demonstrates that mitochondrial autoantibodies can be measured in SLE and APS patients via common methods.
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over Becker, Xu, Ghebrehiwet, and Kurian in view of Zuk et al. (U.S. Patent No. 4208479).
While Becker, Xu, Ghebrehiwet, and Kurian make obvious the method of claims 37-40, 43-48, and 51 as discussed above, they do not recite all the reagents together in a kit.
However, Zuk et al. teaches the convenience and accuracy enhancement associated with combining all necessary reagents for an assay together in a kit (column 22, lines 20-68).
Therefore, it would have been obvious to one of ordinary skill in the art to assemble together the reagents (C1qBP autoantigenic polypeptide and reagents for the detection of the autoantibodies, etc.) in the form of a kit, in order to create an assay kit diagnosis or determining the progression in SLE in a sample from a subject as described by Becker, Xu, Ghebrehiwet, and Kurian. 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.
Conclusion
For all the reasons discussed above, claims 37-52 are rejected and therefore no claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER JOSEPH HOFFMAN whose telephone number is (571)272-9080. The examiner can normally be reached 10:00-6:30 M-F.
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/ALEXANDER J. HOFFMAN/ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/ Supervisory Patent Examiner, Art Unit 1677
August 3, 2026
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