DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/24/2025 has been entered.
Previous Election/Restrictions
The present Application is presently filed as a DIVISIONAL of 15/577,631.
For clarity, it is noted that Applicant’s previous election (as noted in the Non-Final Rejection of 11/07/2023) was as follows:
The Election filed 6/30/2023 in response to the Office Action of 5/15/2023 was acknowledged and had been entered.
Applicant's election of the following species was acknowledged: Species (a1): CA125 as a single marker; Species (b1): EOC as the type of gynecological disease; Species (c1): anti-CA125 monoclonal antibody as the type of binding agent; Species (d2): nanoparticle with labels , Eu(III). Claims 9-10,22 drawn to a non-elected species a, claims 14-16, drawn to a non-elected species d, were withdrawn from further consideration as drawn to non-elected species.
The election had been treated as an election without traverse (MPEP § 818.03(a)). As the requirement for restriction was deemed proper, was maintained and was thereby made FINAL.
Therefore, presently, claim(s) 9, 10, 14-16, and 22 has/have been withdrawn. Claims 4 and 21 have been canceled. Claim(s) 28 is/are new. Claims 1-3, 5--8, 11-13, 17-20, 23-28 are subject to examination below.
Note: The examiner of record has changed.
Priority
The present application was filed on 05/01/2020 and is a DIV of 15/577,631, filed 11/28/2017. Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/FI2016/050490, filed 07/04/2016. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. FI20155531, filed on 07/03/2015 in FI.
Information Disclosure Statement
The Information Disclosure Statement(s) (IDS), entered on 05/01/2020 is/are in compliance with the provisions of 37 CFR 1.97 and has/have been considered in full/part. A signed copy of list of references cited from the/each IDS is included with this Office Action.
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(s) 28 is/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 pre-AIA the applicant regards as the invention.
Claim 28, recites the limitations "said gynecological disease" in line 9 . There is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
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.
Claim(s) 2 and 23 is/are rejected 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, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 fails to specify a further limitation of the subject matter claimed, because it fails to further limit claim 1, since it currently recites “wherein the kit is for an assay for determining…”. With respect to said recitation, it is noted that the recitations appear to be drawn to the intended use of the kit, which do not further limit the structural limitations of the claimed kit (device).
Claim 23 is rejected based on its dependency of rejected claim 2.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claim(s) 1-3, 5-8, and 24 is/are rejected under U.S.C. 103(a) as being unpatentable over Chen et al. (J. PROTEOME RES., vol. 12, no. 3, 1 March 2013 pages 1408-1418 and Supplement, IDS Reference) in view of Akita et al. (Int J Gynecol Cancer 2012;22: 531Y538), Kuno et al. (Multilectin assay for detecting fibrosis-specific glyco-alteration by means of lectin microarray, Clinical Chemistry 57:1 48–56 (2011), Previously published online at DOI: 10.1373/clinchem.2010.151340), and Beatson et al. (PLoS ONE, 10(5) The Breast Cancer-Associated Glycoforms of MUC1, MUC1-Tn and sialyl-Tn, Are Expressed in COSMC Wild-Type Cells and Bind the C-Type Lectin MGL: 2015, e0125994. doi:10.1371/journal.pone.0125994).
Regarding claim 1:
Chen et al. teaches: an immune assay for CA125 comprising a CA125 binding agent in a labeled sandwich format (i.e. a cancer antigen 125 (CA125)-binding agent-lectin-sandwich assay) (e.g. Fig. 1).
In particular, Chen et al. teaches a CA125 immunoassay which comprises a monoclonal antibody which binds CA125 (i.e. a CA125-binding agent) (i.e. wherein said CA125-binding agent is a monoclonal antibody) (e.g. Fig. 1C, depicted bottom antibody attached to a solid surface, CA125 antigen depicted as glycoforms with ribbon decorated with squares, circles, and diamonds; Pg. 1410, Preparation of Antibody Capture Microarrays, monoclonal antibodies to CA125), in other words Chen et al. teaches the use of a monoclonal antibody to CA125 immobilized on a solid surface as the capture agent;
and
that the lectin which binds the analyte CA125 is labeled (i.e. wherein either said CA125-binding agent or said lectin comprises a detectable label) (e.g. Fig. 1, the lectin or antibody binding the CA125 is labeled, label depicted as star in Fig. 1C), in other words, Chen teaches using a lectin as the detection agent which binds to the captured CA125 analyte and that the detection agent (the lectin) is labeled to provide a signal.
The teaching of Chen et al. of a cancer antigen 125 (CA125)-binding agent-lectin-sandwich assay, comprising a CA125-binding agent which is a monoclonal antibody, and a lectin comprising a detectable label, contains the pieces claimed to perform the assay (e.g. Fig. 1C, depicted bottom antibody attached to a solid surface, CA125 antigen depicted as glycoforms with ribbon decorated with squares, circles, and diamonds; Pg. 1410, Preparation of Antibody Capture Microarrays, monoclonal antibodies to CA125), in other words Chen et al. teaches "reagents for an immunoassay" in which an anti-CA125 antibody is used as a capturing agent and a biotinylated lectin binds to the Tn antigen on the captured CA125, which is then detected by a labeled secondary antibody. This description of reagents and a specific assay format strongly implies the components and methodology that would constitute a kit.
Although Chen et al. teaches that the CA125 is detected via a labeled lectin, Chen et al. doesn’t explicitly teach that the lectin is a macrophage galactose-type lectin (MGL).
However, Akita et al. teaches that it is known in the art that CA125 comprises sTn or sialyl- Tn as well as Tn, and that sTn is a known marker associated with cancer and in particular that sTn is correlated with ovarian cancer (e.g. “Conclusions: Estimation of the sTn/MUC16 level may be useful for discriminating endometriosis from ovarian cancer” Pg. 531; CA125 is encoded by the MUC16 gene and is a type I membrane glycoprotein comprising a long extracellular domain, a transmembrane domain, and a short cytoplasmic domain, the extracellular domain of MUC16 is highly modified with a variety of N- and O-glycans,4 which function as ligands for its binding partners” Pg. 532 1st ¶).
Importantly, Akita et al. provides the crucial motivation to target specific glycoforms of CA125. Akita teaches that CA125 (encoded by the MUC16 gene) is a heavily glycosylated mucin that contains the Sialyl-Tn (sTn) antigen (p. 532, "the extracellular domain of MUC16 is highly modified with a variety of N- and O-glycans"). Crucially, Akita establishes the sTn antigen as a clinically significant biomarker for ovarian cancer, “Sialyl-Tn antigen (Neu5Ac>2-6GalNAc-O-Ser/Thr) is one of the tumor-associated mucin-type carbohydrate antigens”, noting that it “is used as a diagnostic marker for ovarian cancer” and its serum level "is elevated in 50% of patients with ovarian cancer compared with patients with benign gynecological diseases" and that its presence correlates with a "lower 5-year survival rate" (p. 532, 2nd ¶). Therefore Akita et al. teaches that it was known in the art that CA125 comprises s-Tn antigen, and that this antigen was known to be elevated and associated with lower survival rates.
Akita explicitly suggests that "an approach targeting the specific glyco-alteration on some proteins may have great potential for improving the diagnostic accuracy for cancer prediction.17,18” and references for example “18. Kuno A, Ikehara Y, Tanaka Y, et al. Multilectin assay for detecting fibrosis-specific glyco-alteration by means of lectin microarray.” .” Kuno et al., as referenced by Akita, is a reference which also acknowledges the knowledge in the art that multiple types of lectins are known binding partners for glycol-alterations (e.g. Pg. 532 3rd ¶, Pg. 537 reference 18).
Therefore, Akita provides a strong motivation to specifically detect the sTn-containing glycoform of CA125 to create a more diagnostically and prognostically powerful assay than the generic assay taught by Chen.
Akita et al. further teaches that the use of kits is well known in the art (e.g. “report developing a "sandwich enzyme-linked immunosorbent assay (ELISA)" Pg. 534, right Col. 1st P; “detected with a Chemilumi-One chemiluminescence Kit” Pg. 533. Left Col. 1st P).
Although the teachings of Chen et al. and Akita et al. disclose that CA125 comprises the antigen sTn (glycoalterations), neither Chen et al. nor Akita et al. explicitly teach that MGL binds CA125, however Beatson et al. teaches that it is known in the art that MGL binds sTn (e.g. “Here we show that not only can MUC1-Tn interact with MGL, but also the sialyated derivative MUC1-STn can bind this lectin” Pg. 3, 2nd P).
Beatson et al. also teaches that:
“Aberrant glycosylation occurs in the majority of human cancers, and changes in mucin-type O-glycosylation are key events that play a role in the induction of invasion and metastases, and generates novel cancer-specific glyco-antigens which can interact with cells of the immune system” (e.g. Pg. 2, abstract); and
Immobilization of MGL: “MGL was immobilized to the surface by conjugating the primary amine groups to the aldehyde groups of the immobilized cross-linking agent” (e.g. Pg. 5, also Fig. 2)
Relevantly, Beatson et al. teaches the specific tool necessary to achieve the goal set forth by Akita. Beatson teaches that MGL is a known, specific binding partner for the sTn antigen when present on mucins ("Here we show that not only can MUC1-Tn interact with MGL, but also the sialyated derivative MUC1-STn can bind this lectin," p. 3, 2nd Para.). This directly provides the teaching of the missing MGL element from the claim.
Beatson also teaches that using kits is well known in the art (e.g. teaches using a proximity ligation assay kit, Pg. 8, 3rd P).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the CA125 sandwich immune assay of Chen comprising labeling CA125 with a labeled lectin, as taught by Chen, by replacing Chen’s generic detection lectin with the lectin MGL as taught by Beatson et al., because the motivation was known in the art as taught by Akita et al., who teaches that targeting the sTn antigen on CA125 would improve the diagnostic and prognostic value of the assay. It would have been further obvious to replace the lectin taught by Chen, with the lectin MGL taught by Beatson, by recognizing that CA125 comprises a known desirable component such as sTn, as taught by Akita et al. and combining this knowledge with the teaching in the art that MGL binds sTN, as taught by Beatson et al., in order to replace the lectin taught by Chen with the lectin MGL taught by Beatson et al., because all three references in the art of mucin research teach that it is known in the art that CA125 and Mucins are a marker of interest in assaying for cancer (e.g. Chen et al.: “that the identified glycoforms (CA125, STn-CA125, and SLeX-CA125) are able to differentiate early epithelial ovarian cancer (EOC) from benign disease.” They further note that this novel glycoprofiling "might improve differential diagnosis and management of ovarian cancer" (Page 248, in the first full ¶),” "introduction" section, Chen et al. reiterate their primary objective: to develop a glycoprofiling method for serum CA125 and MUC1 to improve the current CA125 serum test for differentiating primary epithelial ovarian cancer (EOC) from benign and borderline ovarian neoplasms, and to improve the diagnostic utility of existing CA125 serum assays” (Page 253, first ¶); Akita et al.: “CA125 antigen is a useful marker for ovarian cancer” ( Pg. 207, first ¶, Pg. 210, first ¶), (Pg. 210, first ¶) ; Beatson et al.: “that aberrant glycosylation is a common feature in most human cancers, leading to the creation of novel cancer-specific glyco-antigens. They specifically mention Tn and STn as two glyco-epitopes found expressed by many carcinomas, which can be carried on mucin-type glycoproteins. They also highlight that tumor-associated STn is linked to poor prognosis and chemotherapy resistance” (Pg.226, Abstract, Pg. 275, Discussion), which would motivate one of ordinary skill in the art to search for more selective binding partners of interest for CA125. In particular, the teaching of Akita that “Sialyl-Tn antigen” “is one of the tumor-associated mucin-type carbohydrate antigens” and it “is used as a diagnostic marker for ovarian cancer. The serum level of sialyl-Tn antigen is elevated in 50% of patients with ovarian cancer compared with patients with benign gynecological diseases and healthy controls” and that “sialyl-Tn antigen positive patients with ovarian cancer have a lower 5-year survival rate than sialyl-Tn antigen negative ones.” (Pg. 532 2nd ¶)., would motivate one of ordinary skill in the art to assay for CA125 by selecting to bind to the s-Tn antigen known to be found in CA125 and other mucins, in order to improve the diagnosis of cancer patients since Akita teaches that s-Tn is a “tumor-associated mucin-type carbohydrate antigen” which is “elevated in 50% of patients with ovarian cancer compared with patients with benign gynecological diseases” which in turn would provide a desirable binding target for one of ordinary skill in the art to selectively bind to.
One would have been further motivated to replace the lectin which binds to CA125, as taught by Chen, with the lectin MGL, because Beatson teaches that MGL is a functional and selective alternative ligand for binding sTn found on a lectin, and because the combined teachings of Chen et al. and Akita et al. elucidate that sTn (which is found on CA125) is a tumor-associated mucin-type carbohydrate antigen known to be elevated in patients with ovarian cancer. Beatson provides the known lectin (MGL) to accomplish this targeted detection. The combination is merely the use of a known lectin (MGL from Beatson) to detect its known ligand (sTn from Beatson) on a known target protein (CA125 from Akita) within a conventional assay framework (the sandwich assay from Chen).
One of ordinary skill in the art would have had a reasonable expectation of success in combining these teachings because the sequential binding elements are known to effectively function and exist in the protein and component structure taught by the art, meaning it is known in the art that CA125 is a mucin and that, in cancer, mucins comprise aberrant glycosylation (Chen et al. and Beatson et al. teachings discussed supra), that it is known in the art that CA125 comprises the glycosylated s-Tn antigen, a tumor-associated mucin-type carbohydrate antigen known to be elevated in cancers (Akita et al. discussed supra), and it is known in the mucin binding art that MGL binds specifically to s-Tn. Therefore, one would have had a reasonable expectation of success by substituting the lectin which binds CA125 (as taught in Chen et al. discussed supra) be the lectin MGL (as taught by Beatson et al. discussed supra) because MGL can bind to CA125 through the known sTn carbohydrate antigen component of CA125.
One of ordinary skill in the art would have had a further reasonable expectation of success in making this combination, because the individual components are all well-established in the art: (1) sandwich immunoassays are routine (Chen et al. discussed supra); (2) CA125 is known to be the target analyte and to present the sTn antigen (Akita et al. discussed supra); and (3) the MGL-sTn binding interaction is specific and robust (Beatson et al. discussed supra). Furthermore, Beatson demonstrates that MGL can be immobilized on a surface for binding assays (p. 5; Fig. 2), confirming its suitability for use in a kit format like Chen's. As such, combining these known elements to achieve the predictable result of detecting sTn-CA125 would require no undue experimentation.
In addition, it would have been further prima facie obvious to assemble the reagents of Chen et al. in kits to allow for detection of ovarian cancer by measuring cancer specific glycoprotein markers including CA 125(MUC16) and MUC1 as taught in Chen et al., and to assemble reagents for analysis into a kit format because both Akita et al. and Beatson et al. teach that kits are well known in the art of assays, one would have been further motivated to assemble the reagents taught into a kit format for convenience and for improving reproducibility in screening biological samples for diagnosis and management of the disease.
Regarding claim 2, Chen et al. teaches that they “demonstrate that aberrant -glycoforms of CA125 (MUC16) and MUCI (CA15-3) are present in serum from primary iEOC patients and can be detected with O-glycan specific monoclonal antibodies and lectins (Pg. 1409 last Par., Figure 1.) (i.e. for an assay for determining a gynaecological disease state in a subject, wherein the gynaecological disease is selected from the group consisting of epithelial ovarian cancer (EOC), endometriosis, and endometrial cancer).
Regarding claims 3 and 24, Chen in view and Akita and Beatson teach a kit with a labeled MGL lectin as discussed supra. Beatson et al. also teaches: that the “Two glyco-epitopes that are found expressed by many carcinomas are Tn” “and STn” and that “These glycans can be carried on many mucin-type glycoproteins” (Abstract). Beatson also teach, as discussed supra, that MGL is a known, specific binding partner for the sTn antigen when present on mucins (Pg. 3, 2nd ¶).
Beatson doesn’t explicitly teach that the MGL is a nanoparticle-immobilized MGL (MGL-NP) or that the kit further comprises nanoparticles for immobilizing said MGL.
However, Beatson further discuss particles for labeling in their methods section: “Binding of MUC1 glycoproteins and glycopeptides to MGL expressing cells: Biotinylated glycopeptides or glycoproteins were bound for 2h to FITC streptavidin beads” here they describe preparing biotinylated glycopeptides or glycoproteins and their subsequent binding to FITC streptavidin beads for MGL cell-binding assays (Pg. 5, 3rd ¶, Fig. 4 legend) (which reads on nanoparticle immobilized MGL, because the specification defines “the term “nanopartide” (NP) refers to a particle, synthetic or natural, having one or more dimensions, e.g. a diameter, of less than about 1000 nm, e.g. about 500 nm or less, …” “As used herein, the term “about” refers to a range of values ±10% of a specified value” (see at [0065]), which encompasses particles which are for example 1100 nm or 1.1 um, which encompass microparticles). In these teachings, the FITC streptavidin beads are a type of particle used for labeling and detection. These fluorescent beads also read on “wherein said detectable label is a fluorescent label), as in claim 24.
Beatson further teaches immobilization of MGL: “MGL was immobilized to the surface by conjugating the primary amine groups to the aldehyde groups of the immobilized cross linking agent” (e.g. Pg. 5, also Fig. 2)
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effectively filing date of the invention to modify the label bound to the lectin MGL in the immunoassay, as taught by Chen in view of Akita and Beatson by having the label be a bead label bound to MGL (i.e. a nanoparticle-immobilized MGL, as in claim 3) as taught by Beatson et al. in order to take advantage of the modularity of utilizing a label such as a FITC streptavidin bead for example which would allow the accessible form of assay using fluorescence detection methods (a fluorescent label, as in claim 24), because Beatson teaches that this type of bead can be functionalized to bind to MGL (e.g. Pg. 5, 3rd ¶, Fig. 4 legend). It would have been further obvious to modify the kit taught by Chen, Akita, and Beatson, to further comprise the labeled beads taught by Beatson (i.e. nanoparticles for immobilizing said MG), as part of standard methods for proving a complete kit with all the necessary components, for example the components for labeling and detecting. One would have had a reasonable expectation of success if modifying the label of MGL (taught by Chen, Akita, and Beatson) with a labeled fluorescent particle because Beatson further teaches the flexibility of immobilization of MGL: “MGL was immobilized to the surface by conjugating the primary amine groups to the aldehyde groups of the immobilized cross linking agent” (e.g. Pg. 5, also Fig. 2), which makes it adaptable to being functionalized or immobilized on multiple surfaces, for example on fluorescent particles.
Regarding claim 5, Chen et al. teaches: that the monoclonal antibody which binds CA125 is bound to a solid surface (i.e. said CA125-binding agent is bound to a solid surface) (e.g. Fig. 1C, depicted bottom antibody attached to a solid surface, CA125 antigen depicted; Pg. 1410, Preparation of Antibody Capture Microarrays, monoclonal antibodies to CA125, immobilizing a human monoclonal antibody to CA-125 i.e. X52 to a microarray support (page 1410, left 2nd ¶), in other words Chen et al. teaches the use of a monoclonal antibody to CA125 immobilized on a solid surface as the capture agent.
Regarding claim 6, Chen et al. teaches: immobilizing a human monoclonal antibody to CA-125 i.e. X52 to a microarray support (page 1410, left 2nd ¶) and teaches that teach a "gold standard assay” (detecting CA125 in a sample with antibodies in a “double antibody sandwich ELISA") (Pg. 1414). ELISA (Enzyme-Linked Immunosorbent Assay) is a technique inherently performed in microtiter plates. Furthermore, Akita et al. directly and explicitly describe the use of microtiter plates for their experiments. They state, "Enzyme-Linked Immunosorbent Assay Monoclonal antibody against CA125 antigen was absorbed onto Maxisorp Immunoplate.” Maxisorp Immunoplates are a common brand of microtiter plates. (i.e. said CA125-binding agent is bound to a microtiter plate).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the microarray support of Chen et al. by including a microtiter plate as taught by Akita et al., in order to have the advantages offered by microtiter plates, for example in immunoassay experiments, the advantage of assaying for titers of reagents. One would be motivated to include a microtiter plate, in accordance with well-known procedures for immunoassays, since the steps are conventional and well understood as shown by those in the field as taught by Chen, and Akita, and Beatson (Beatson for example also refer to a type of multi-well plate in their supplementary information. Specifically, S1 Fig. in the "Supporting Information" describes a binding assay where "1μg of recombinant MUC1-Tn or MUC1-STn was coated onto each well of a 9 well dish" [270, S1 Fig]. A "9 well dish" is a format of a multi-well plate, functionally equivalent to a microtiter plate for the purpose of coating wells for an assay).
Regarding claim 7, with respect to the limitation a control sample "for comparing to the measured value [..] Chen et al. teach various control samples i.e. some treated with Neu some not treated, for comparison. In addition, Chen et al. teach gold standard assay i.e. detecting CA125 in a sample with antibodies in a double antibody sandwich ELISA for comparing diagnostic utility (Fig. 3; page 1414 left last paragraph), which also reads on a “control sample”. Furthermore, determining elevated levels in the assays of Chen, Akita, and Beatson, necessarily requires a comparison to a control absent any limitations on "control". For example, Akita et al. teach that they developed a "sandwich enzyme-linked immunosorbent assay (ELISA)", which typically employs standard curves for quantitative determination. They explicitly state that a "standard curve (optical density vs amount of biotinylated MLS132 mAb) was generated" to convert optical density readings into quantifiable amounts of bound antibody. These standards act as control samples with known concentrations (Pg. 534, right Col, 2nd ¶). Beatson et al. teach that For MGL binding assays, they use "MUC1 carrying the core 1 (T antigen) or unglycosylated MUC1" as negative controls, which showed no significant binding compared to baseline (Fig. 3. control = secondary antibody only, Fig. 4, legend, isotype control). In summary, all three references demonstrate a robust scientific approach by consistently incorporating various forms of control samples and measurements, which are fundamental for interpreting their results and establishing the validity of their findings regarding CA125 and mucin-lectin interactions
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to assemble the reagents of Chen et al. in kits to allow for detection of ovarian cancer by measuring cancer specific glycoprotein markers including CA125 and further include a control sample as a positive control to validate the reagents and levels of detection (i.e. a control sample for comparing to a measured value of CA125 binding to MGL) in accordance with known procedures in assays including immunoassays. One would be motivated to include a control sample for comparing to a measured value of CA125 binding to MGL in accordance with well-known procedures for measuring levels of an analyte since the steps are conventional and well understood as shown by those in the field as taught by Chen, Akita and Beatson.
Regarding claim 8, Chen et. al. teaches assaying the sample to determine CA125 concentration (Pg. 1410 left Col. 3rd ¶) wherein the subjects have CA125 levels between 30-500KU/L (Pg.1409 right Col. last ¶), which are considered elevated (Pg. 1408 left ¶) (i.e. one or more reagents for assaying CA125 protein concentration).
Claim(s) 11, 12, 13, 17-20, 23, 25, 26, and 28 is/are rejected under U.S.C. 103(a) as being unpatentable over , over Chen et al. (J. PROTEOME RES., vol. 12, no. 3, 1 March 2013 pages 1408-1418 and Supplement, IDS Reference) in view of Akita et al. (Int J Gynecol Cancer 2012;22: 531Y538), Kuno et al. (Multilectin assay for detecting fibrosis-specific glyco-alteration by means of lectin microarray, Clinical Chemistry 57:1 48–56 (2011), Previously published online at DOI: 10.1373/clinchem.2010.151340), and Beatson et al. (PLoS ONE, 10(5) The Breast Cancer-Associated Glycoforms of MUC1, MUC1-Tn and sialyl-Tn, Are Expressed in COSMC Wild-Type Cells and Bind the C-Type Lectin MGL: 2015, e0125994. doi:10.1371/journal.pone.0125994), as applied to claims 1-3, 5-8, and 24 above, further in view of Harma et. al. (Clin. Chem; 2001, 47:3, 561-2001, IDS reference).
Regarding claims 11, 12, 13, 17-20, 23, 25, 26, and 28 Chen et al., Akita et al., and Beatson, teach the immunoassay comprising beads as discussed supra.
Beatson et al. is silent as to the size and material of the beads used in the assay, Chen et al., Akita et al., and Beatson, don’t explicitly teach that the particles comprise Europium III, or that the nanoparticle is doped with luminescent lanthanide ions.
However, Harma et al. teaches throughout the publication and especially in the abstract, that “Streptavidin was covalently coated on 107-nm nanoparticles containing >30 000 europium molecules entrapped” (Pg. 561, Methods), and using commercially available long lifetime fluorescent europium chelate nanoparticles, 107 nm in diameter (Pg.562, left Col, 2nd ¶), to improve detection limits in miniature as well as conventional biochemical assays (Abstract) . The europium nanoparticle label is suitable for detection of any biotinylated molecule either in solution or on a solid phase (Abstract). (i.e. the dimensions of said nanoparticle are less than about 1000 nm, about 500 nm or less, about 100 nm or less, as in claim 11).
Harma et al. further teaches properties of the nanoparticles which comprise that:
“The most successful time-resolved fluorescence technology, the commercial DELFIA concept (Perkin-Elmer Life Sciences), is based on the enhanced signal produced by lanthanide ions as they are dissociated and successively entrapped by b-diketones, detergents, and synergistic agents” (i.e. nanoparticle is doped with luminescent lanthanide ions, as in claim 18); that they
“previously have shown that 10 000 intrinsically fluorescent europium chelates (nondissociative) can be monitored on a single microparticle by a confocal time-resolved fluorometer.” (i.e. nanoparticle is doped with luminescent lanthanide ions with luminescence emission in visible wavelengths, as in claim 18), (i.e. detectable label is a nanoparticle comprising a detectable fluorescent or chemiluminescent label, as in claim 26); that
“To further improve the sensitivity provided by nondissociative labels, we describe here a europium-label detection technology applicable to various bioanalyses. These nanosized polymer labels contain .30 000 europium molecules entrapped by b-diketones, which possess one of the highest quantum yields of the known lanthanide chelators.” (Pg. 562, 1st ¶) (i.e. nanoparticle is doped with europium (III), as in claim 19 and claim 20), (i.e. detectable label is a lanthanide chelate, europium(III)), as in claim 25); that
The nanoparticles can be imaged at long exposures, for example “We used a 45-s exposure time to image the nanoparticles” (Pg. 567, right Col. 2nd ¶) (which reads on, nanoparticle with luminescence emission in visible wavelengths and long fluorescence decay, as in claim 18); and that
the nanoparticles comprise polystyrene nanoparticles (Pg. 562, Materials and Methods, Nanoparticles) (i.e. polystyrene nanoparticles, as in claim 12).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the immunoassay to detect CA125 with a detectable label, as taught by Chen et al., Akita et al., and Beatson et al., by substituting the detectable label with nanoparticles which are doped with 3" lanthanide europium (III), wherein the dimensions of said nanoparticle are less than about 1000 nm, about 500 nm or less, about 100 nm or less, as in claim 11; and the nanoparticle is doped with luminescent lanthanide ions with luminescence emission in visible wavelengths, as in claim 18; the detectable label is a nanoparticle comprising a detectable fluorescent or chemiluminescent label, as in claim 26; nanoparticle is doped with europium (III), as in claim 19 and claim 20; the detectable label is a lanthanide chelate, europium(III)), as in claim 25; the nanoparticle with luminescence emission in visible wavelengths and long fluorescence decay, as in claim 18; polystyrene nanoparticles, as in claim 12, as taught by Harma et al. in order to improve the detection of the assay, because Harma et al. teaches that “The most successful time-resolved fluorescence technology, is based on the enhanced signal produced by lanthanide ions as they are dissociated and successively entrapped by b-diketones”; that they “previously have shown that 10 000 intrinsically fluorescent europium chelates (nondissociative) can be monitored on a single microparticle by a confocal time-resolved fluorometer”; and that “These nanosized polymer labels contain .30 000 europium molecules” “which possess one of the highest quantum yields of the known lanthanide chelators.” (Pg. 562, 1st ¶), which provide the advantages of having enhanced signal production, single microparticle detection, with “one of the highest quantum yields,” which make the these labels a highly desirable design choice in an immunoassay. Furthermore, the detectable label with nanoparticles which are doped with 3" lanthanide europium (III), wherein the dimensions of said nanoparticle are less than about 100 nm or less, provide the advantage of single nanoparticle detection with such doping and size; and doping with luminescent lanthanide ions with luminescence emission in visible wavelengths provides the flexibility of visual detection with high quantum yields, which a detectable fluorescent label, also provides. One would have had a reasonable expectation of success in combining these nanoparticles which are doped with 3" lanthanide europium (III) with the assays taught by Chen et al., Akita et al., and Beatson et al., because Beatson teaches that MGL can be effectively immobilized onto surfaces (Immobilization of MGL: “MGL was immobilized to the surface by conjugating the primary amine groups to the aldehyde groups of the immobilized cross-linking agent” (e.g. Pg. 5, also Fig. 2)).
Regarding claim 13, Harma et al. teaches:
Qualitative (Visualization): The paper explicitly states that individual nanoparticles were visualized in microtiter wells using a time-resolved fluorescence microscope (i.e. the nanoparticles are directly or indirectly qualitatively or quantitatively detectable) (e.g. In Fig. 6, images of the same microtiter wells measured for the biotinylated PSA dilution curve (above) were taken with the time-resolved fluorescent microscope, Fig. 3A - an image of nanoparticles).
Quantitative: The authors determined the detection limits of the nanoparticles in solution using a standard time-resolved plate fluorometer. They report that "one single 408-nm nanoparticle was detected in solution," and also that this is a direct quantitative measurement of the nanoparticles, since they teach that “The detection limits of the nanoparticles were measured in 200 mL of the 1 mL/L Triton X-100 solution with the standard time-resolved plate fluorometer. As shown in Fig. 2, one single 408-nm nanoparticle was detected in solution, and the detection limits for the 210- and 107-nm particles were 8 and 75, respectively.” (i.e. the nanoparticles are directly or indirectly qualitatively or quantitatively detectable) (Pg. 565, right Col, 1st ¶).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effectively filling date of the invention to modify the immunoassay to detect CA125 with a detectable label, as taught by Chen et al., Akita et al., and Beatson et al., by having the detectable label be nanoparticles which are directly or indirectly qualitatively or quantitatively detectable, as taught by Harma et al. in order to improve the flexibility of detection of the assay, because Harma et al. teaches that these labels provide both very effective qualitative and quantitative detection options. One would be motivated to have assays with both effective qualitative and quantitative detection options in accordance with well-known procedures for immunoassays since the steps are conventional and well understood as shown by those in the field as taught by Harma et al.
Regarding claim 17, Harma et al. teaches that “The concentration of chelated europium(III) ions in the nanoparticles was 80 mmol/L, which would apparently cause an inner-filter effect when applied to rapidly decaying fluorophores (11 ). It is not uncommon that rapidly decaying fluorophores self-quench in micromolar concentrations. However, when lanthanide chelates are used, no such effect has been found even in high (millimolar) concentrations.” Which reads on “nanoparticle is doped with a lanthanide chelate”, as in claim 17 (Pg. 565, left Col. 2nd ¶).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effectively filing date of the invention to modify the immunoassay to detect CA125 with a detectable label, as taught by Chen et al., Akita et al., and Beatson et al., by substituting the detectable label with nanoparticle is doped with a lanthanide chelate, as taught by Harma et al. in order to improve the detection of the assay, because Harma et al. teaches that “The most successful time-resolved fluorescence technology, is based on the enhanced signal produced by lanthanide ions as they are dissociated and successively entrapped by b-diketones”; that they “previously have shown that 10 000 intrinsically fluorescent europium chelates (non-dissociative) can be monitored on a single microparticle by a confocal time-resolved fluorometer” (Pg. 562, 1st ¶), which provide the advantages of having enhanced signal production” which make the these labels an improved option for labeling the analyte in an immunoassay. One would have had a reasonable expectation of success in combining these nanoparticle is doped with a lanthanide chelate with the assays taught by Chen et al., Akita et al., and Beatson et al., because Beatson teaches that MGL can be effectively immobilized onto surfaces (Immobilization of MGL: “MGL was immobilized to the surface by conjugating the primary amine groups to the aldehyde groups of the immobilized cross-linking agent” (e.g. Pg. 5, also Fig. 2)).
Regarding claims 23 and 28, Chen et al., Akita et al., and Beatson, teach the immunoassay comprising a kit for assaying CA-125 as discussed supra, comprising:
said gynaecological disease is epithelial ovarian cancer (EOC)) (as in claims 23 and 28) (e.g. Chen et al. teaches that they “demonstrate that aberrant -glycoforms of CA125 (MUC16) and MUCI (CA15-3) are present in serum from primary iEOC patients and can be detected with O-glycan specific monoclonal antibodies and lectins (Pg. 1409 last Par., Figure 1.));
said CA125-binding agent is an anti-CA125 monoclonal antibody (as in claim 23) (i.e. a CA125-binding agent, as in claim 28) (wherein said CA125-binding agent is a monoclonal antibody bound to a solid surface, as in claim 28) (i.e. (i.e. A kit for a cancer antigen 125 (CA125)-binding agent-lectin-sandwich assay, as in claim 28) (e.g. Chen et al. teaches a CA125 immunoassay which comprises a monoclonal antibody which binds CA125 (i.e. a CA125-binding agent) (i.e. wherein said CA125-binding agent is a monoclonal antibody) (e.g. Fig. 1C, depicted bottom antibody attached to a solid surface, CA125 antigen depicted as glycoforms with ribbon decorated with squares, circles, and diamonds; Pg. 1410, Preparation of Antibody Capture Microarrays, monoclonal antibodies to CA125));
a macrophage galactose-type lectin (MGL), as in claim 28, (e.g. Beatson et al. teaches that it is known in the art that MGL binds sTn (e.g. “Here we show that not only can MUC1-Tn interact with MGL, but also the sialyated derivative MUC1-STn can bind this lectin” Pg. 3, 2nd ¶);
said MGL is a nanoparticle-immobilized MGL, as in claims 23 and 28 (e.g. Beatson further discuss particles for labeling in their methods section: “Binding of MUC1 glycoproteins and glycopeptides to MGL expressing cells: Biotinylated glycopeptides or glycoproteins were bound for 2h to FITC streptavidin beads” here they describe preparing biotinylated glycopeptides or glycoproteins and their subsequent binding to FITC streptavidin beads for MGL cell-binding assays (Pg. 5, 3rd ¶, Fig. 4 legend) (which reads on nanoparticle immobilized MGL, as in claims 23 and 28) (i.e. wherein said MGL comprises a detectable label, as in claim 28); as discussed supra-,
With respect to the recitations of: “said kit is for assaying CA-125 as a single marker” (claims 23 and 28), it is noted that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. In the instant case, although Chen et al. do not specifically employ the terminology of the intended use recitations, since the reference teaches a device which meets the structural limitations of the instant claims, the device taught would necessarily be capable of being used in the manner recited in the instant claims. Furthermore, Chen et al. describes Microarray Glycoprofiling of CA125 and discusses characterizing specific glycopatterns of CA125 that may have diagnostic significance (e.g. abstract) which may allow the platform of Chen et al. to perform the intended use, since the reference meets the limitations and also contemplates assaying for CA125 in particular. If the prior art structure is capable of performing the intended use, then it meets the claim.
Chen et al., Akita et al., and Beatson et al. do not explicitly teach that the labeled particle comprises nanoparticles are doped with 3" lanthanide europium (III).
However, Harma et al, as discussed supra, teach:
properties of the nanoparticles which comprise that “The most successful time-resolved fluorescence technology” “is based on the enhanced signal produced by lanthanide ions as they are dissociated and successively entrapped by b-diketones, detergents, and synergistic agents”; that they
“previously have shown that 10 000 intrinsically fluorescent europium chelates (nondissociative) can be monitored on a single microparticle by a confocal time-resolved fluorometer”, and that ‘These nanosized polymer labels contain .30 000 europium molecules entrapped by b-diketones, which possess one of the highest quantum yields of the known lanthanide chelators.” (Pg. 562, 1st ¶) (i.e. nanoparticles which are doped with 3" lanthanide europium (III)).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effectively filing date of the invention to modify the immunoassay to detect CA125 with a detectable label, as taught by Chen et al., Akita et al., and Beatson et al., by substituting the detectable label with nanoparticles which are doped with 3" lanthanide europium (III), as taught by Harma et al. in order to improve the detection of the assay, because Harma et al. teaches that “The most successful time-resolved fluorescence technology, is based on the enhanced signal produced by lanthanide ions as they are dissociated and successively entrapped by b-diketones”; that they “previously have shown that 10000 intrinsically fluorescent europium chelates (nondissociative) can be monitored on a single microparticle by a confocal time-resolved fluorometer”; and that “These nanosized polymer labels contain >30000 europium molecules” “which possess one of the highest quantum yields of the known lanthanide chelators.” (Pg. 562, 1st ¶), which provide the advantages of having enhanced signal production, single microparticle detection, with “one of the highest quantum yields,” which make the these labels a highly desirable design choice in an immunoassay. One would have had a reasonable expectation of success in combining these nanoparticles which are doped with 3" lanthanide europium (III) with the assays taught by Chen et al., Akita et al., and Beatson et al., because Beatson teaches that MGL can be effectively immobilized onto surfaces (Immobilization of MGL: “MGL was immobilized to the surface by conjugating the primary amine groups to the aldehyde groups of the immobilized cross linking agent” (e.g. Pg. 5, also Fig. 2)).
Claim(s) 27 is/are rejected under U.S.C. 103(a) as being unpatentable over , over Chen et al. (J. PROTEOME RES., vol. 12, no. 3, 1 March 2013 pages 1408-1418 and Supplement, IDS Reference) in view of Akita et al. (Int J Gynecol Cancer 2012;22: 531Y538), Kuno et al. (Multilectin assay for detecting fibrosis-specific glyco-alteration by means of lectin microarray, Clinical Chemistry 57:1 48–56 (2011), Previously published online at DOI: 10.1373/clinchem.2010.151340), and Beatson et al. (PLoS ONE, 10(5) The Breast Cancer-Associated Glycoforms of MUC1, MUC1-Tn and sialyl-Tn, Are Expressed in COSMC Wild-Type Cells and Bind the C-Type Lectin MGL: 2015, e0125994. doi:10.1371/journal.pone.0125994), as applied to claims 1-3, 5-8, and 24 above, and further in view of (KR 20140011760, IDS Reference).
Regarding claim 27 Chen et al., Akita et al., and Beatson, teach the immunoassay comprising labels as discussed supra.
Chen et al., Akita et al., and Beatson, don’t explicitly teach that said detectable label is a nanoparticle inherently detectable by being an upconverting nanoparticle (UCNP), resonance particle, quantum dot or gold particle.
Regarding claim 27, KR 20140011760 teach throughout the patent and especially in Fig 1, an antibody-lectin sandwich method and reagents for measuring cancer specific glycoprotein markers comprising capturing the marker with an antibody specific to the marker (Fig 1 element 3) to form a complex and detecting the complex with a lectin (Fig.1 element 6) coupled to a labeled nanoparticle (instant claim 13) as for example gold nanoparticle, quantum dots, fluorescence polystyrene bead (see Fig 1 caption and Fig 1 element 5).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the immunoassay to detect CA125 with a detectable label, as taught by Chen et al., Akita et al., and Beatson et al., by substituting the detectable label with gold, as taught by KR 20140011760 in order to improve the detection options of the assay, because this type of label is inherently visible.
Response to Arguments
Applicant's arguments filed 05/01/2024 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to examined claims have been considered but are moot in light of the new grounds of rejection which are necessitated by Applicant’s amendment and because the arguments do not apply to the combination of references being used in the current rejection.
Conclusion
No claims are allowed.
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/DANIELA E FUENTES/
Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 July 31, 2025