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 .
Priority
The present application was filed on 03/13/2024. This application is a 371 of PCT/EP2022/075496 09/14/2022 which claims benefit of EUROPEAN PATENT OFFICE (EPO) 21196556.1 09/14/2021.
Claim Status
Claim 17 is canceled. Claims 1-16, and 18-19 are pending.
Specification
The disclosure is objected to because of the following informalities: page 25 line 32 “others=2)”, it appears that an opening parenthesis is missing.
Appropriate correction is required.
Claim Objections
Claims 1 and 8 are objected to because of the following informalities:
Claim 1 par.2 recites “a binding agent capable to bind…”, which is grammatically incorrect. Please fix it, e.g., capable of binding.
Claim 1 par.3 recites “wherein presence or overexpression of mammaglobin-A is indicative for being at risk for and/or for presence of breast cancer”. The phrase should be fixed as -indicative of being at risk for and/or the presence of breast cancer-.
Claim 1 par.4 “a glycan structure” should be -the glycan structure-.
Claim 1 par.5 recites “is indicative for said subject to be at risk for or to suffer from breast cancer.” The phrase should be fixed as - is indicative of said subject being at risk for or suffering from breast cancer-.
Claim 8 line 2 and claim 9 lines 2-5: objecting to limitations “PHA or WFL” in claim 8, “AAL, UEA-I, LCA, PSL, AAA, LTA, HPA, LBA, PhoSL, AOL, VVA”, “TJA-I, SCA, WGA, SNA, MAA II, Con A, GNA, MGL, NPA”, “DBA”, “RCA I, RCA 120” in claim 9 as they are in abbreviation forms while they are firstly mentioned in the claim set. Please replace the abbreviation limitations in the claims with the full, unabbreviated technical terms.
Appropriate correction is required.
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 1-16 and 18-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions (natural products, abstract idea) without significantly more.
Step 1 – Whether a claim is to a statutory category?
Yes. Claims 1-12 are drawn to a method. Claims 13-16 and 18-19 are drawn to a kit.
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?)
As explained in MPEP § 2106.04(II), a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim.
The inventions of claims 1-16 and 18-19 are drawn to a method and a kit for diagnosing whether a subject may be at risk for or may suffer from breast cancer. This involves using a binding agent that can bind to a glycan structure of mammaglobin-A, which is a biomarker glycoprotein associated with breast cancer.
The claimed method, claims 1-12, recites a law of nature because the naturally occurring correlation between levels of a specific marker and the health condition (e.g., cancer) is set forth in the claims. Claim 1 states the level of mammaglobin-A is compared to that in a control sample, which is an abstract idea that involving assessing the comparison of expression level of the biomarker in a test sample, and then making an evaluation or judgment as to whether the subject may be at risk for or may suffer from breast cancer. The comparing and determining steps could be performed in the human mind, or by a human using pen and paper. It reads on comparing levels and drawing conclusions from the comparison about whether the subject may be at risk for or may suffer from breast cancer.
The claimed kit, claims 13-16 and 18-19, contains natural compound, e.g., lectin or antibody.
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.
In claim 1, the additional steps of contacting a sample with a binding agent and comparing the binding of said binding agent to said glycan structure of mammaglobin-A in the test sample to that in a control are insufficient to integrate the exception into a practical application because the purpose is merely to obtain data. Claims 2-16 and 18-19 do not recite any additional element that integrate the exception into a practical application of the exception.
There is no subsequent step 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 subject is determined to be at risk for or suffer from breast cancer.
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.
In claim 1, the additional steps are contacting a sample with a binding agent and comparing the binding of said binding agent to said glycan structure of mammaglobin-A in the test sample to that in a control. Claims 8-12 and 16 recite using lectin-based assay and lectins in the diagnosing method of claim 1. Claims 13-15 and 18-19 recite a kit comprising a binding agent that can bind to a glycan structure of mammaglobin-A, e.g., lectins and anti-mammaglobin-A antibody.
These additional elements are well-understood, routine, conventional activities previously known to the industry. This position is supported by Fling (WO2002053017), Xiong et al. (Use of a lectin affinity selector in the search for unusual glycosylation in proteomics, Journal of Chromatography B, 782 (2002) 405–418), and Lastovickova et al. (Use of Lectin-based Affinity Techniques in Breast Cancer Glycoproteomics: A Review, J.Proteome Res. 2020, 19, 1885-1899).
Fling teaches compositions, methods, and kits for the diagnosis of breast cancer, which are based on detecting the presence of mammaglobin epitopes in a sample (see Abstract). The compositions include antibodies that bind to mammaglobin in a glycan structure of mammaglobin-A (see page 10 lines 15-20; see page 5 lines 20-27; see page 13 lines 23-30, see page 66 Example 10, seq id no 27 represents mammaglobin A). The complex of the antibody and mammaglobin is then detected using a detection reagent, e.g., lectin (see page 38 lines 6-13). Therefore, the method and kit comprise lectin and anti-mammaglobin-A antibody.
Xiong teaches that glycoproteins and unusual forms of glycosylation can be important indicators of disease, e.g., forming alpha-Fuc(1→6)-b-GlcNAc-Asn in breast cancer. See page 405 Introduction, see page 406 col.1 par.1. Xiong demonstrates that that fucose-containing glycopeptides can be selected by lectin affinity chromatography (see page 418 col.1 par.2). Xiong further concludes “based on affinity chromatography that derivatization of proteins with alpha-Fuc(1→6)-b-GlcNAc-Asn occurs in the case of at least one known cancer marker. Because this type of glycosylation is structurally unique and targetable, it provides an easy way to search for cancer markers in the future” (see page 418 col.1 par.3).
Lastovickova teaches that changes in glycoprotein content, altered glycosylations, and aberrant glycan structures are increasingly recognized as cancer hallmarks (see Abstract). The analysis of the glycoprotein composition and the specific glycoforms appears to be a promising goal in the search of biomarkers for the diagnosis and prognosis of breast cancer (see page 1894 col.2 par.1). Lastovickova teaches that the glycan part of the glycoproteins can be captured and detected by specific antibodies or lectins (see page 1886 col.1 last par.; page 1889 col.1 par.1). Lectin-based affinity techniques are used for glycoproteomic studies of breast-cancer-related glycoproteins (see Abstract).
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).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 5, 13 and 19 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Fling et al. (WO2002053017 – IDS dated 3/13/2024).
For claim 1, claim 1 recites “a method for diagnosing whether a subject may be at risk for or may suffer from breast cancer, comprising
(1) contacting a sample obtained from said subject, said sample comprising mammaglobin-A as a biomarker glycoprotein, with a binding agent capable to bind to a glycan structure of mammaglobin-A,
wherein presence or overexpression of mammaglobin-A is indicative of being at risk for and/or the presence of breast cancer, and
wherein said glycan structure deviates from the glycan structure of mammaglobin-A as expressed in a subject not being at risk for or suffering from breast cancer, and
(2) determining whether said binding agent bound to a glycan structure of mammaglobin-A,
wherein lower or higher binding of said binding agent to said glycan structure of mammaglobin-A compared to a control sample is indicative for said subject to be at risk for or to suffer from breast cancer.”
Fling teaches compositions and methods for the diagnosis of breast cancer, which are based on detecting the presence of mammaglobin epitopes in a sample (see Abstract). The mammaglobin comprises mammaglobin A (see page 13 lines 23-30, page 66 Example 10, seq id no 27 represents mammaglobin A). The compositions include antibodies that bind to mammaglobin in a glycosylation-sensitive manner (see page 10 lines 15-20), for example, antibodies bind to a glycosylation site of mammaglobin with an affinity that is dependent on glycosylation (see page 22 lines 1-20). Fling also teaches that, compared to normal cells, protein glycosylation is often altered in tumor cells (see page 22 lines 1-20). This teaching implies that the glycan structure of mammaglobin as expressed in the subject with tumor cells deviates from the glycan structure of mammaglobin as expressed in a subject without tumor cells. This teaching anticipates the limitation that the antibodies could have lower or higher affinity for the glycan structure (i.e., glycosylation site) of mammaglobin in the test sample compared to a control sample (e.g., a sample from a subject having normal cells) because the affinity of antibodies to a glycosylation site of mammaglobin is dependent on glycosylation (see page 22 lines 1-20). Thus, lower or higher binding of said binding agent to the glycan structure of mammaglobin in the test sample compared to a control sample is indicative of said subject being at risk for or suffering from breast cancer.
The method of diagnosing breast cancer includes: (a) contacting a biological sample obtained from a patient with a binding agent that binds to a polypeptide; (b) detecting in the sample an amount of polypeptide that binds to the binding agent; and (c) comparing the amount of polypeptide with a predetermined cut-off value, and therefrom determining the presence or absence of a cancer in the patient. See page 5 lines 20-27. The polypeptide comprises a variant of a native mammaglobin epitope, e.g., mammaglobin variant A (see page 13 lines 23-30, page 66 Example 10, seq id no 27 represents mammaglobin A).
For claim 2, Fling teaches the method according to claim 1. Fling teaches the subject is a human (see page 5 lines 20-27: teaching a method of diagnosing breast cancer in a patient, page 35 lines 24-25: teaching a "patient" refers to any warm-blooded animal, preferably a human).
For claim 5, Fling teaches the method according to claim 1. Fling teaches the binding agent is anti-glycan antibody (see page 10 lines 15-20, page 22 lines 1-20: teaching the antibodies bind to a glycosylation site of mammaglobin).
For claims 13 and 19, Fling teaches the method according to claim 1. Fling also teaches a kit for performing the method of claim 1 (see page 47 lines 1-10). The kit comprises a monoclonal antibody or fragment thereof that specifically binds to a mammaglobin epitope (see page 47 lines 1-10), wherein the mammaglobin is mammaglobin-A (see page 66 Example 10).
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.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Fling et al. (WO2002053017) in view of Lastovickova et al. (Use of Lectin-based Affinity Techniques in Breast Cancer Glycoproteomics: A Review, J.Proteome Res. 2020,19,1885−1899) and Scott et al. (Glycosylation and its implications in breast cancer, Expert Rev Proteomics. 2019 August ; 16(8): 665–680).
For claim 3, Fling teaches the method according to claim 1. Fling does not teach breast cancer is characterized by being Her2-negative; estrogen receptor (ER)-negative, progesterone receptor-negative (PR) and Her2-negative (triple-negative); or estrogen receptor-positive, progesterone receptor-positive and Her2-negative.
Lastovickova teaches breast cancer typically does not produce any symptoms when the tumor is small and easiest to treat (see page 1888 par.2). Early cancer detection and the consequential choice of appropriate therapeutics are essential for an accurate diagnosis to decrease the possibility of metastasis and relapse (see page 1888 par.2). Breast cancer is a highly complex systemic disease with various tumor subtypes (page 1887 part 3). Molecular subtypes of breast cancer can be identified by using classical immunohistochemistry markers, including the recognition of hormone (estrogen or progesterone) receptors (ER+/ER−; PR+/PR−) and the level of human epidermal growth factor receptor 2 (HER2 gene; HER2+/HER2−) (see page 1884 par.1, Table 1). The glycoprotein composition or the analysis of specific glycoforms can be used as possible biomarkers for early cancer detection, determination of tumor stage, and prognosis or as a biomarkers for evaluating the efficacy of therapeutics in cancer treatment (see page 1887 col.2 par.3).
Scott teaches that breast cancer is a highly complex systemic disease with various tumor subtypes based on the presence of hormone (estrogen or progesterone) receptors and the level of human epidermal growth factor receptor 2 (see page 3 par.2). Despite triple negative breast cancers only representing approximately 10-15% of all breast cancers, these tumors are characterized by occurrence in a younger patient population, high proliferative activity and a relatively poor outcome. Moreover, the targeted therapies are ineffective in patients with triple negative breast cancer (see page 3 par.2). Assessing tumor specific glycosylation patterns has the potential to add to current therapies because it provides information needed to develop a patient-specific treatment plan that could avoid common issues such as drug resistance, recurrence and metastasis (see page 12 par.1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the method of Fling for diagnosing breast cancer characterized by triple negative test ER-/PR-/HER2-, because triple negative breast cancer has a relatively poor outcome and there is no effective treatment for triple negative breast cancer patients as taught by Scott. Thus, detecting the changes associated with glycan structures in breast cancer will help to detect cancer in an early phase to decrease the possibility of metastasis and relapse in breast cancer (see Lastovickova page 1887 col.2 par.3) and help develop a patient-specific treatment plan (Scott page 9 paragraph 3).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Fling et al. (WO2002053017) in view of Bernstein et al. (Identification of Mammaglobin as a Novel Serum Marker for Breast Cancer, Clin Cancer Res 2005;11(18) September 15, 2005).
For claim 4, Fling teaches the method according to claim 1. Fling does not teach breast cancer comprises invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), ductal carcinoma of no special type (NST) or invasive lobular carcinoma (ILC).
Bernstein teaches that the expression of mammaglobin is highly specific in breast cancer, e.g., the protein was detectable by immunostaining in 72% of breast tumors and not in other tumor types (see Abstract), wherein the breast tumors comprise lobular or ductal carcinoma in situ (see page 6530 Table 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the method of Fling for diagnosing breast cancer, which comprises lobular carcinoma or ductal carcinoma in situ, because Bernstein shows that about 72% of lobular carcinoma or ductal carcinoma in situ has positive for mammaglobin expression. Using mammaglobin protein as a serum biomarker for early detection of breast cancer impacts the management and treatment of patients with breast cancer (see Bernstein Abstract).
Claims 6-12 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Fling et al. (WO2002053017) in view of Lastovickova et al. (Use of Lectin-based Affinity Techniques in Breast Cancer Glycoproteomics: A Review, J.Proteome Res. 2020,19,1885−1899).
For claims 6 and 7, Fling teaches the method according to claim 1. Fling teaches that the antibodies bind to a glycosylation site of mammaglobin (see page 22 lines 1-20). Fling does not clearly teach the binding agent binds to one or more of any one of core fucose or a glycan structure terminating in N-acetylgalactosamine (GalNAc).
Lastovickova teaches that changes in glycoprotein content, altered glycosylations, and aberrant glycan structures are increasingly recognized as cancer hallmarks (see Abstract). The analysis of the glycoprotein composition and the specific glycoforms appears to be a promising goal in the search of biomarkers for the diagnosis and prognosis of breast cancer (see page 1894 col.2 par.1). Lastovickova teaches that the glycan part of the glycoproteins can be captured and detected by specific antibodies or lectins (see page 1886 col.1 last par.; page 1889 col.1 par.1). Lectin-based affinity techniques are used for glycoproteomic studies of breast-cancer-related glycoproteins (see Abstract). Lastovickova also summarizes lectins used in glycoproteomic studies of human breast cancer samples, focusing on new potential breast cancer markers (see Table 4). In particular, AAL lectin binds to the glycan structures containing core fucose Fuc(α1−3)[Gal(β1−4)] GlcNAc (see page 1890 Table 4). This teaching encompasses the limitation in claim 6. Also, various lectins bind to the glycan structures terminating in N-acetylgalactosamine (GalNAc) (see page 1890 Table 4). This teaching encompasses the limitation in claim 7.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Fling, using the agent that can bind to alpha-Fuc(1→6)-b-GlcNAc-Asn or a glycan structure terminating in GalNAc for diagnosing breast cancer as taught by Lastovickova because Fling is generic to an agent that can bind to a glycosylation site of mammaglobin and Lastovickova specifically teaches that alpha-Fuc(1→6)-b-GlcNAc-Asn and glycan structures terminating in GalNAc are potential breast cancer related glycan structures of glycoproteins, e.g., mammaglobin (see page 1889 col.1 par.2; page 1893 col.2 par.1: teaching that βGal-βGalNAc structures plays at least a partial role in the progression of breast cancer).
One of ordinary skill in the art would have been motivated to use the agent that can bind to alpha-Fuc(1→6)-b-GlcNAc-Asn or a glycan structure terminating in GalNAc for diagnosing breast cancer with a reasonable expectation of success because Lastovickova teaches these glycan structures above are breast cancer related glycan structures (see page 1889 col.1 par.2).
For claim 8, Fling teaches the method according to claim 1. Fling does not teach that the binding agent binds to the same glycan structure as PHA or WFL or a combination thereof with an affinity of at least 80% of the affinity with which PHA or WFL or a combination thereof binds to said glycan structure.
See the discussion of Lastovickova in claim 6 above. Lastovickova further teaches that PHA lectins bind to the glycan structures containing bisecting GlcNAc, GalNAc, bi- and triantennary N-acetyllactosamine glycans containing β1,6-linked branch etc. Lastovickova teaches that WFA lectin (i.e., WFL) binds to GalNAc(α1−3/6)Gal, GalNAc(β1−3/6)Gal (see page 1890 Table 4). These glycan structures above are potential breast cancer related glycan structures (see page 1889 col.1 par.2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Fling, using the agent that can bind to the same glycan structure as PHA or WFL for diagnosing breast cancer because Fling is generic to an agent that can bind to a glycosylation site of mammaglobin and Lastovickova specifically teaches that the glycan structures which bind to PHA or WFL are potential breast cancer related glycan structures (see page 1889 col.1 par.2; page 1893 col.2 par.1: teaching that βGal-βGalNAc structures plays at least a partial role in the progression of breast cancer; Table 4).
One of ordinary skill in the art would have been motivated to use the agent that can bind to the same glycan structure as PHA or WFL for diagnosing breast cancer with a reasonable expectation of success because Lastovickova teaches the glycan structures which bind to PHA or WFL are breast cancer related glycan structures (see page 1889 col.1 par.2; Table 4).
For claims 9-10, Fling teaches the method according to claim 1. Fling does not teach that the binding agent is WFL or PHA.
See the discussion of Lastovickova in claim 6 above. Lastovickova teaches that PHA lectins bind to the glycan structures containing bisecting GlcNAc, GalNAc, bi- and triantennary N-acetyllactosamine glycans containing β1,6-linked branch etc. Lastovickova teaches that WFA lectin (i.e., WFL) binds to GalNAc(α1−3/6)Gal, GalNAc(β1−3/6)Gal (see page 1890 Table 4). These glycan structures above are potential breast cancer related glycan structures (see page 1889 col.1 par.2).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Fling, using WFL or PHA lectins for diagnosing breast cancer because Fling is generic to an agent that can bind to a glycosylation site of mammaglobin, and Lastovickova specifically teaches that PHA or WFL can bind to the breast cancer related glycan structures of glycoprotein, e.g., mammaglobin (see page 1889 col.1 par.2; page 1893 col.2 par.1: teaching that βGal-βGalNAc structures plays at least a partial role in the progression of breast cancer; Table 4).
One having ordinary skill in the art would have been motivated to use lectin to detect the glycan structure in mammaglobin proteins as an obvious matter to try an art known technique for detecting a protein via its glycan structure. One of ordinary skill in the art would have had a reasonable expectation of success in using lectin in diagnosing breast cancer because the binding agent of Fling and lectins of Lastovickova are functionally equivalent in detecting the glycan structure of proteins.
For claims 11-12, Fling teaches the method according to claim 1. Fling teaches a method for the diagnosis of breast cancer based on detecting alterations of mammaglobin glycan structure in a sample (see Abstract, see page 10 lines 15-20). Fling teaches using ELISA with the monoclonal antibodies to identify mammaglobin glycosylation sites (see page 13 lines 20-22). Fling does not teach a lectin-based assay, e.g., ELLBA or MELLBA.
See the discussion of Lastovickova in claim 6 above. Lastovickova teaches that the glycan part of the glycoproteins can be captured and detected by specific antibodies or lectins (see page 1886 col.1 last par.; page 1889 col.1 par.1). Enzyme-linked lectin assay (ELLA) is analogous to the conventional standard ELISA technique but uses lectins as agents instead of the antibodies. ELLA is used to detect glycoproteins with pathologically altered glycan chains (see page 1886 col.1 last par., col.2 par.1 and 5).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Fling, using lectin-based assay ELLBA for diagnosing breast cancer as taught by Lastovickova because the ELLBA can detect alterations of glycan structures in the protein so that it can be used for diagnosing breast cancer as taught by Fling. One of ordinary skill in the art would have been motivated to use lectin to detect the glycan structure in mammaglobin proteins as an obvious matter to try a known technique for detecting a protein via its glycan structure. One of ordinary skill in the art would have had a reasonable expectation of success in using lectins in diagnosing breast cancer, because the binding agent of Fling and lectins of Lastovickova are functionally equivalent in detecting the alterations of glycan structures of proteins. Moreover, ELLA is analogous to the conventional standard ELISA technique but uses lectins as agents instead of the antibodies (see Lastovickova page 1886 col.2 par.5).
For claims 14-15, Fling teaches the kit according to claim 13 comprising a monoclonal antibody or fragment thereof that specifically binds to a mammaglobin epitope (see page 47 lines 1-10). Fling teaches the kit is for ELISA (see page 13 lines 20-22). Fling does not teach the binding agent is lectin which is PHA or WFL.
See the discussion of Lastovickova in claim 6 above. Lastovickova teaches that the glycan part of the glycoproteins can be captured and detected by specific antibodies or lectins (see page 1886 col.1 last par.; page 1889 col.1 par.1). Enzyme-linked lectin assay (ELLA) is analogous to the conventional standard ELISA technique but uses lectins as agents instead of the antibodies. ELLA is used to detect glycoproteins with pathologically altered glycan chains (see page 1886 col.1 last par., col.2 par.1 and 5). Lastovickova further teaches PHA lectins bind to the glycan structures containing bisecting GlcNAc, GalNAc, bi- and triantennary N-acetyllactosamine glycans containing β1,6-linked branch etc.; or WFA lectin (i.e., WFL) binds to GalNAc(α1−3/6)Gal, GalNAc(β1−3/6)Gal (see page 1890 Table 4). These glycan structures above are potential breast cancer related glycan structures (see page 1889 col.1 par.2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the kit taught by Fling, using lectin as a binding agent in the kit because the lectins can detect alterations of glycan structures in the protein so that it can be used for diagnosing breast cancer as taught by Fling. Accordingly, the binding agents of Fling can be replaced by WFL or PHA lectin as taught by Lastovickova. One of ordinary skill in the art would have been motivated to use lectin to detect the glycan structure in mammaglobin proteins as an obvious matter to try a known technique for detecting a protein via its glycan structure wherein the glycan structure is a marker of breast cancer as taught by Lastovickova (see Lastovickova Table 4). One of ordinary skill in the art would have had a reasonable expectation of success in using lectins in the breast cancer diagnostic kit because the binding agent of Fling and lectins of Lastovickova are functionally equivalent in detecting the alterations of glycan structures of proteins and ELLA is analogous to the conventional standard ELISA technique but uses lectins as agents instead of the antibodies (see page 1886 col.2 par.5).
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Fling et al. in view of Lastovickova et al., as applied to claim 10, and further in view of Liu et al. (Glycosylation patterns and PHA-E-associated glycoprotein profiling associated with early hepatic encephalopathy in Chinese hepatocellular carcinoma patients, Am J Transl Res 2016;8(10):4250-4264), and Xiong et al. (Use of a lectin affinity selector in the search for unusual glycosylation in proteomics, Journal of Chromatography B, 782 (2002) 405–418).
For claim 16, Fling and Lastovickova teach the method according to claim 10. Fling teaches that, compared to normal cells, protein glycosylation is often altered in tumor cells (see page 22 lines 1-20). Fling does not teach the binding agent is a combination of PHA and WFL.
See the discussion of Lastovickova in claim 6 above. Lastovickova teaches that aberrant protein glycosylation, changes in glycoprotein concentrations, as well as the alteration of the glycan structure are currently accepted as signs of cancer. Thus, the glycoprotein composition or the analysis of specific glycoforms can be used as possible biomarkers for early cancer detection, determination of tumor stage, and prognosis or as biomarkers for evaluating the efficacy of therapeutics in cancer treatment (see page 1887 col.2 par.3). Plenty of potential breast cancer related glycan structures are introduced (see Table 4). In general, lectin specificity allows the detection of some glycoproteins that cannot be detected by conventional methods (see page 1894 col.2 par.5). Lastovickova teaches that lectin-based affinity techniques, e.g., lectin microarray or ELLA, are used for the high-throughput screening of glycan differences in breast cancer samples (see Abstract, page 1892 col.2 par.1 and 5). Lastovickova also teaches when combining lectins with various glycan affinities into an assay, it increased the detection coverage and the robustness of the approach and provided a complex view of the glycoproteome (see page 1895 col.1 par.1).
Liu teaches that there are various glycoproteins secreted or shed from cell surfaces or released from tissue into serum, which enables serum as the most available sample to be the primary clinical specimen in disease diagnosis and biomarker discovery (see page 4260 col.1 Discussion). Liu performs a lectin microarray to analyze the different glycosylation patterns in serum proteins from the cancer patients, e.g., GalNAc, terminal α-1,3 Man, bisecting GlcNAc, (GlcNAc) n, O-GlcNAc, Neu5Ac, tetra-antennary complex-type N-glycan and GalNAc α/β1-3/6 Gal (see page 4261 col.2 par.3, Fig.3). The lectin microarray for detecting glycosylation structures of serum proteins comprises 50 lectins, e.g., PHA and WFL (see Abstract, page 4252 Lectin microarray, Fig.2A). Liu teaches that PHA has a strong capacity and specific recognition for the bisecting N-acetylglucosamine (bisecting GlcNAc) or tetra-antennary complex-type N-glycan and WFL binds to GalNAc α/β1-3/6 Gal (see page 4256 col.1 par.2, col.2 par.1).
Xiong teaches that glycoproteins and unusual forms of glycosylation can be important indicators of disease. For example, the level of b(1→6)GlcNAc branched oligosaccharides increases in breast cancer. See page 405 col.1. However, the detection of the unusual form of glycosylation was a challenge because alterations of glycan structure and concentration can be caused by unknown ways (see page 405 col.2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Fling and Lastovickova, using a combination of lectins (e.g., PHA and WFL) in lectin-based techniques as taught by Lastovickova and Liu for diagnosing breast cancer because Liu teaches that an assay using a combination of lectins can bind to variety of glycosylation sites of proteins in serum samples of patients, particularly, GlcNAc and GalNAc (see page 4256 col.1 par.2) which are breast cancer related glycan structures as taught by Lastovickova and Xiong. One of ordinary skill in the art would have been motivated to combine PHA and WFL to detect the glycan structure in mammaglobin because the combination can detect more alterations of glycan structure of proteins which are presence in breast cancer as taught by Xiong and Lastovickova. The combination also increases detection coverage and the robustness of the approach and provides a complex view of the glycoproteome (Lastovickova page 1895 col.1). One of ordinary skill in the art would have had a reasonable expectation of success in using a combination of lectins in diagnosing breast cancer because Liu and Lastovickova show that multi-lectin microarray can detect various glycan alterations in an assay.
For claim 18, Fling teaches the kit according to claim 13. Fling teaches that, compared to normal cells, protein glycosylation is often altered in tumor cells (see page 22 lines 1-20). Fling does not teach the binding agent is a combination of PHA and WFL.
See the discussion of Lastovickova in claim 6 above. Lastovickova teaches that aberrant protein glycosylation, changes in glycoprotein concentrations, as well as the alteration of the glycan structure are currently accepted as signs of cancer. Thus, the glycoprotein composition or the analysis of specific glycoforms can be used as possible biomarkers for early cancer detection, determination of tumor stage, and prognosis or as biomarkers for evaluating the efficacy of therapeutics in cancer treatment (see page 1887 col.2 par.3). Plenty of potential breast cancer related glycan structures are introduced (see Table 4). In general, lectin specificity allows the detection of some glycoproteins that cannot be detected by conventional methods (see page 1894 col.2 par.5). Lastovickova teaches that lectin-based affinity techniques, e.g., lectin microarray or ELLA, are used for the high-throughput screening of glycan differences in breast cancer samples (see Abstract, page 1892 col.2 par.1 and 5). Lastovickova also teaches when combining lectins with various glycan affinities into an assay, it increased the detection coverage and the robustness of the approach and provided a complex view of the glycoproteome (see page 1895 col.1 par.1).
Liu teaches that there are various glycoproteins secreted or shed from cell surfaces or released from tissue into serum, which enables serum as the most available sample to be the primary clinical specimen in disease diagnosis and biomarker discovery (see page 4260 col.1 Discussion). Liu performs a lectin microarray to analyze the different glycosylation patterns in serum proteins from the cancer patients, e.g., GalNAc, terminal α-1,3 Man, bisecting GlcNAc, (GlcNAc) n, O-GlcNAc, Neu5Ac, tetra-antennary complex-type N-glycan and GalNAc α/β1-3/6 Gal (see page 4261 col.2 par.3, Fig.3). The lectin microarray for detecting glycosylation structures of serum proteins comprises 50 lectins, e.g., PHA and WFL (see Abstract, page 4252 Lectin microarray, Fig.2A). Liu teaches that PHA has a strong capacity and specific recognition for the bisecting N-acetylglucosamine (bisecting GlcNAc) or tetra-antennary complex-type N-glycan and WFL binds to GalNAc α/β1-3/6 Gal (see page 4256 col.1 par.2, col.2 par.1).
Xiong teaches that glycoproteins and unusual forms of glycosylation can be important indicators of disease. For example, the level of b(1→6)GlcNAc branched oligosaccharides increases in breast cancer. See page 405 col.1. However, the detection of the unusual form of glycosylation was a challenge because alterations of glycan structure and concentration can be caused by unknown ways (see page 405 col.2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the kit of Fling, using a combination of lectins (e.g., PHA and WFL) in lectin-based techniques as taught by Lastovickova and Liu for diagnosing breast cancer because Liu teaches that a combination of lectins can bind to variety of glycosylation sites of proteins in serum samples of patients, particularly, GlcNAc and GalNAc (see page 4256 col.1 par.2) which are breast cancer related glycan structures as taught by Lastovickova and Xiong. One of ordinary skill in the art would have been motivated to combine PHA and WFL in a kit to detect the glycan structure in mammaglobin because the combination can detect more alterations of glycan structure of proteins which are presence in breast cancer as taught by Xiong and Lastovickova. The combination also increases detection coverage and the robustness of the approach and provides a complex view of the glycoproteome (Lastovickova page 1895 col.1). One of ordinary skill in the art would have had a reasonable expectation of success in using a combination of lectins in diagnosing breast cancer because Liu and Lastovickova show that lectin microarray can detect various glycan alterations in an assay.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 1-2, 5-16, and 18-19 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 6-16 and 18 of copending Application No. 18/685,864 (‘864) in view of Fling et al. (WO2002053017). Although the claims at issue are not identical, they are not patentably distinct from each other because:
For claims 1 and 19, claim 1 of ‘864 teaches a method for diagnosing whether a subject may be at risk for or may suffer from cancer, comprising (1) contacting a sample obtained from said subject, said sample comprising a biomarker glycoprotein, with a binding agent capable of binding to a glycan structure of said biomarker glycoprotein, wherein presence or overexpression of said biomarker glycoprotein is indicative for risk for and/or presence of said cancer, and wherein said glycan structure deviates from the glycan structure of said biomarker glycoprotein as expressed in a subject not being at risk for or suffering from said cancer, and (2) determining whether said binding agent bound to a glycan structure of said biomarker glycoprotein, wherein lower or higher binding of said binding agent to said glycan structure of said biomarker glycoprotein compared to a control sample is indicative for said subject to be at risk for or to suffer from cancer. Claim 1 of ‘864 recites the same method as in claim 1 of the instant application with the difference of a biomarker. Claim 1 of ‘864 does not teach the biomarker is mammaglobin-A.
Fling teaches compositions and methods for the diagnosis of breast cancer, which are based on detecting the presence of mammaglobin epitopes in a sample (see Abstract). The compositions include antibodies that bind to mammaglobin in a glycosylation-sensitive manner (see page 10 lines 15-20), for example, antibodies bind to a glycosylation site of mammaglobin with an affinity that is dependent on glycosylation (see page 22 lines 1-20). Fling also teaches that, compared to normal cells, protein glycosylation is often altered in tumor cells (see page 22 lines 1-20). This teaching implies that the glycan structure of mammaglobin as expressed in the subject with tumor cells deviates from the glycan structure of mammaglobin as expressed in a subject without tumor cells. Therefore, it is obvious to expect that the antibodies can have lower or higher affinity to the glycan structure (i.e., glycosylation site) of mammaglobin in the test sample compared to a control sample (e.g., a sample from a subject having normal cells) because the affinity of antibodies to a glycosylation site of mammaglobin is dependent on glycosylation.
Thus, lower or higher binding of said binding agent to the glycan structure of mammaglobin in the test sample compared to a control sample is indicative of said subject being at risk for or suffering from breast cancer.
The method of diagnosing breast cancer includes: (a) contacting a biological sample obtained from a patient with a binding agent that binds to a polypeptide; (b) detecting in the sample an amount of polypeptide that binds to the binding agent; and (c) comparing the amount of polypeptide with a predetermined cut-off value, and therefrom determining the presence or absence of a cancer in the patient. See page 5 lines 20-27. The polypeptide comprises a variant of a native mammaglobin epitope, e.g., mammaglobin variant A (see page 13 lines 23-30, page 66 Example 10, seq id no 27 represents mammaglobin A).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the method of ‘864 for diagnosing a subject who may be at risk for or may suffer from breast cancer by using mammaglobin A as a biomarker with a reasonable expectation of success because the methods of ‘864 and Fling are identical. Fling shows evidence that using a binding agent capable of binding to the glycan structure of mammaglobin A can diagnose breast cancer.
For claim 2, see claim 2 of ‘864.
For claim 5, see claim 4 of ‘864.
For claim 6, see claim 6 of ‘864.
For claim 7, claim 7 of ‘864 encompasses the limitation of the claim.
For claims 8-10, claims 8-10 of ‘864 encompass the limitations of the claims.
For claim 11, see claim 11 of ‘864.
For claim 12, see claim 12 of ‘864.
For claim 13, see claim 13 of ‘864.
For claim 14, see claim 14 of ‘864.
For claim 15, claim 15 of ‘864 encompasses the limitation of the claim.
For claim 16, see claim 16 of ‘864.
For claim 18, see claim 18 of ‘864.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/CHAU N.B. TRAN/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 August 21, 2026
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