DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement filed 04/09/2024 has been considered by the examiner.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/IB2021/054808 filed 06/01/2021. Based on the filing receipt, the effective filing date of this application is June 1, 2021 which is the filing date of PCT/IB2021/054808 from which the benefit of priority is claimed.
Status of Claims
Claims 3, 7, 18, 22, 25, and 28 are cancelled.
Claims 1-2, 4-6, 8-17, 19-21, 23-24, and 26-27 are pending and examined herein.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 4-6, 8-17, 19-21, 23-24, and 26-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
Claims 1-2, 4-6, 8-17, 19-21, 23-24, and 26-27 are directed to methods and a kit for measuring thrombospondin 2 (TSP2) in subjects with non-alcoholic fatty liver disease (NAFLD), e.g., byusing antibody binding fragments having binding specificity to TSP2. The only limitation placed on the antibody binding fragment is that has binding specificity to TSP2 and no binding specificity to TSP1, TSP3, TSP4, and TSP5.
Although independent claim 1 does not require any specific binding reagents, the scope of the claims covers methods and kits using a large genus of binding reagents, e.g., antibody binding fragments characterized by substantial variability.
Regarding the predictability or unpredictability in the art, the applicant has attested to the ambiguity of antibody specificity. On p. 7 of the applicant’s specification, the applicant discloses, “Specificity can be relatively determined by binding or competitive assays, using e.g., Biacore instruments. Specificity can be exhibited by, e.g., an about 5: 1, about 10: 1, about 20: 1, about 50: 1, about 100: 1, about 10,000: 1 or greater ratio of affinity/avidity in binding to the specific antigen versus nonspecific binding to other irrelevant molecules” (see, lines 16-31). While specificity can be measured, it is still a relative term that compares specific affinity to nonspecific binding.
The specification only discloses actual reduction to practice of two antibodies having the necessary functional characteristics. On p. 25, the applicant discloses, “Serum TSP2 levels were measured with an enzyme-linked immunosorbent assay (ELISA) kit for human TSP-2, using a pair of monoclonal antibodies which recognized distinct sites of human TSP2 (Antibody and Immunoassay Services, University of Hong Kong)” (see, lines 25-28). The specification only further suggests art-recognized methods of testing antibody binding fragments for specificity.
The disclosure general methods that might be used to test antibody binding fragments is insufficient to describe the claimed genus of aptamers. The Federal Circuit addressed an analogous situation in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004), finding that disclosure of “assays for screening compounds, including peptides, polynucleotides, and small organic molecules to identify those that inhibit the expression or activity of the PGHS-2 gene product,” did not satisfy the written description requirement for claims requiring administration of a “compound that selectively inhibits PGHS-2.” Rochester, 119 F.3d at 918, 927; see also Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company, 598 F.3d 1336, 1344 (Fed. Cir. 2010) (recognizing distinction between requirements for written description and enablement).
Furthermore, there is also no disclosure of any partial structure common to the members of the genus of antibody binding fragments that would correlate with function (in this case, the claimed function of having binding specificity to TSP2 and no binding specificity to TSP1, TSP3, TSP4 and TSP5).
The importance of structure/function correlations was recently highlighted by the courts (Abbvie Deutschland v. Janssen Biotech and Centocor Biologics, App. No. 2013-1338, -1346 (Fed. Cir., July 1, 2014)). The Abbvie case involved antibodies and written description. The court stated: “We have held that “a sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568– 69).”. The courts then further stated: “With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” (emphasis added) and then state: " Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002).
One skilled in the art would not envision the applicant as in possession of the entire genus of antibody binding fragments as claimed since the specification merely suggests art-recognized methods of testing antibody binding fragments in addition to the two examples given.
There is no partial structure or other identifying characteristics disclosed, common to the members of the genus of antibody binding fragments having sufficiently high binding specificity for TSP2, that would allow one skilled in the art to envision that the applicant has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus.
For all of these reasons, the specification does not demonstrate possession of the entire genus of antibody binding fragments having the claimed functional characteristics of specifically binding to TSP2.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 8-9 and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 8-9 recite “advanced liver fibrosis comprises fibrosis about or over grade F3”. The specification discloses, “Use of the term "about" is intended to describe values either above or below the stated value in a range of approx.+/- 10%” (see, p. 10, lines 26-27). It is unclear how to interpret “about grade F3” within the context of the specification’s definition of “about”. Therefore, the metes and bounds of the claims cannot be ascertained.
Claim 12 recites, “lowest detection limit”. The applicant’s claims and specification do not disclose how the “lowest detection limit” is calculated. Furthermore, the “lowest detection limit” is not an established metric within the art. Therefore, the metes and bounds of the claim cannot be ascertained.
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 1-2, 4-6, 8-17, 19-21, 23-24, and 26-27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phe without significantly more.
Under the MPEP, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Natural Laws:
Claim 1 recites, “detecting advanced liver fibrosis when the circulating levels of TSP2 in the sample from the subject are greater than about 3.6 ng/ml”. Claim 10 recites, “wherein advanced liver fibrosis is detected with a sensitivity of about or greater than 80% and specificity of about or greater than 60% when the circulating levels of TSP2 in the sample from the subject are greater than about 3.6 ng/ml”. Claim 11 recites, “wherein advanced liver fibrosis is detected with negative predictive value of about or over 90%”. Claim 14 recites, “detecting risk of developing of advanced liver fibrosis per unit increase in the log- transformed circulating level of TSP2 in the sample from the subject measured in ng/ml”. Claim 15 recites, “wherein the method detects a 2.82 times greater risk of developing advanced liver fibrosis per unit increase in log-transformed circulating level of TSP2 in the sample from the subject”. Claim 16 recites, “wherein detecting the risk of developing of advanced liver fibrosis is for risk within a period between about 0.1 years and about 3 years from step (a)”. Claim 27 recites, “(b) detecting advanced liver fibrosis when the circulating levels of TSP2 in the sample from the subject are greater than about 3.6 ng/ml”.
The claims are directed to the natural relationship/correlation between circulating TSP2 levels and the increased risk of advanced liver fibrosis in patients with NAFLD.
The natural correlation set forth above is considered a judicial exception/law of nature. Similar concepts have been held by the courts to constitute law of nature/natural phenomena, as in the identification of a correlation between the presence of biomarkers in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between circulating levels of TSP2 and increased risk of advanced liver fibrosis in patients with NAFLD. Circulating levels of TSP2 correlate with increased risk of advanced liver fibrosis without any human action.
The circulating levels of TSP2 and increased risk of advanced liver fibrosis in patients with NAFLD is a judicial exception as it exists in principle apart from any human action; the relationship itself therefore cannot form the basis for eligibility.
Abstract Ideas:
Claims 1 and 14 are directed towards “detecting advanced liver fibrosis”. Claim 24 is directed towards “identifying the subject as in need of liver fibrosis treatment”.
The claim limitations of detecting liver fibrosis and identifying subjects in need of treatment may be categorized as abstract ideas, namely mental processes/concepts performed in the human mind. The claims, under its broadest reasonable interpretation, covers performance of detecting advanced liver fibrosis and identifying patients as in need of treatment solely within the human mind, or by a human using pen and paper. Therefore, detecting advanced liver fibrosis and identifying patients as in need of treatment represent abstract ideas.
Step 2A, Prong 2
The above-discussed steps of detecting advanced liver fibrosis and identifying patients as in need of treatment are insufficient to integrate the judicial exception into a practical application because steps corresponding to mental activity, which could be performed in a practitioner’s head, are insufficient to constitute a practical application. In this case, detecting advanced liver fibrosis and identifying patients as in need of treatment represent judicial exceptions and not practical applications thereof.
Claims 1 and 14 also recite, “(a) measuring circulating levels of a biomarker thrombospondin 2 (TSP2)”. Claims 2 and 17 recite, “wherein measuring comprises contacting the sample from the subject with a set of capture reagents, wherein the set of capture reagents comprises one or more antibody binding fragments having a binding specificity to TSP2 and no binding specificity to TSP1, TSP3, TSP4 and TSP5”. Claims 4 and 19 recite, “wherein measuring comprises contacting the sample from the subject with a set of capture reagents comprising two antibody binding fragments, each having a binding specificity to distinct sites of TSP2”. Claims 5 and 20 recite, “wherein the TSP2 is human TSP2”. Claims 6 and 21 recite, “wherein the sample is diluted or undiluted blood or serum, diluted at a ratio between about 1:5 and 1 :500 (v/v) of the sample to a sample dilution buffer”. Claim 10 recites, “wherein advanced liver fibrosis is detected with a sensitivity of about or greater than 80% and specificity of about or greater than 60% when the circulating levels of TSP2 in the sample from the subject are greater than about 3.6 ng/ml”. Claim 11 recites, “wherein advanced liver fibrosis is detected with negative predictive value of about or over 90%”. Claim 12 recites, “wherein measuring is by an immunoassay having a lowest detection limit for TSP2 between about 0.01 ng/ml and about 0.18 ng/ml”. Claim 13 and 23 recite, “wherein the subject has NAFLD and one or more of the diseases selected from the group consisting of metabolic syndrome, type 2 diabetes mellitus, cardiovascular disease (CVD), and chronic kidney disease (CKD)”. Claim 15 recites, “wherein the method detects a 2.82 times greater risk of developing advanced liver fibrosis per unit increase in log-transformed circulating level of TSP2 in the sample from the subject”. Claim 16 recites, “wherein detecting the risk of developing of advanced liver fibrosis is for risk within a period between about 0.1 years and about 3 years from step (a)”. Claim 26 recites, “A kit comprising a set of capture reagents for use in the method of claim 1, wherein the set of capture reagents comprises one or more antibody binding fragments having a binding specificity to TSP2 and no binding specificity to TSP1, TSP3, TSP4 and TSP5, wherein the set of capture reagents comprises two antibody binding fragments, each having a binding specificity to distinct sites of TSP2, and
wherein TSP2 is human TSP2”. Claim 27 recites, “An immunoassay comprising the set of capture reagents of claim 2 for use in a method of non-invasively detecting advanced liver fibrosis in a subject with non-alcoholic fatty liver disease (NAFLD), the method comprising: (a) measuring circulating levels of a biomarker thrombospondin 2 (TSP2) in a sample from the subject, and (b) detecting advanced liver fibrosis when the circulating levels of TSP2 in the sample from the subject are greater than about 3.6 ng/ml”. Such steps of measuring TSP2 and the limitations on the assay for measuring TSP2, such as limitations on the binding agents and the subjects of the assay, are insufficient to integrate the judicial exceptions because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015).
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of claims 1-2, 4-6, 8-17, 19-21, 23-24, and 26-27, including the limitations on the measurement of TSP2 and the limitations on subjects for the measurement, do not add significantly more to the judicial exception. The steps are routine and conventional data gathering, which is not contributing an inventive concept. Furthermore, the limitation of claim 24, “treating the subject to reduce liver fibrosis”, does not add significantly more to the judicial exception because it is recited at high-level without specific treatments that depend on the outcome of the method of claim 1. Therefore, the additional elements of claims 1-2, 4-6, 8-17, 19-21, 23-24, and 26-27 do not add an inventive concept.
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exceptions.
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.
Claims 1-2, 4-6, 10-11, 12, 24, and 26-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kimura (“Serum thrombospondin 2 is a novel predictor for the severity in the patients with NAFLD”, published 2021-01-01, cited in IDS filed 2024-04-09) as evidenced by the package insert for Quantikine® ELISA Human Thrombospondin-2 Immunoassay from R&D Systems by bio-techne.
With respect to claim 1, Kimura teaches a method of non-invasively detecting advanced liver fibrosis in a subject with non-alcoholic fatty liver disease (NAFLD), the method comprising: (a) Measuring circulating levels of a biomarker thrombospondin 2 (TSP2) in a sample from the subject, and (b) detecting advanced liver fibrosis when the circulating levels of TSP2 in the sample from the subject are greater than about 3.6 ng/ml (see, e.g., subjects with NAFLD – p. 506, under “2.1 Patients and clinical examinations”: “We enrolled 130 biopsy-proven Japanese NAFLD patients”; measuring circulating levels of TSP2 in a sample from a subject – p. 507, under “2.1 Patients and clinical examinations”: “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”; detecting advanced liver fibrosis when circulating levels of TSP2 in the sample are greater than 3.6 ng/mL – p. 511, under “TABLE 5”, under “≥F3”, under “Cut-off value” for “TSP2”). While the units are not listed in “TABLE 5” of Kimura, the Cut-off value for TSP2 for liver fibrosis stages ≥F3 is understood to be 28.2 ng/mL because the packages insert for the Quantikine ELISA discloses that the assay measures TSP2 in the ng/mL range (see, e.g., p. 7, under “SERUM/PLASMA/HUMAN MILK ASSAY”).
With respect to claim 2, Kimura teaches measuring comprises contacting the sample with antibodies having specificity for TSP2 and not to TSP1, TSP3, TSP4, and TSP5 (see, e.g., p. 507, under “2.1 Patients and clinical examinations”: “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The specificity is evidenced in the package insert for the Quantikine ELISA (see, e.g., p. 11, under “SPECIFICITY”). The statement “This assay recognizes natural and recombinant human Thrombospondin-2” is understood to mean that the assay uses antibodies that are specific for only TSP2.
With respect to claim 4, Kimura teaches measuring comprises contacting the sample with a set of antibodies having a binding specificity to distinct sites of TSP2 (see, e.g., “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The set of antibodies is evidenced in the package insert for the Quantikine ELISA (see, e.g., p. 2, under “PRINCIPLE OF THE ASSAY”: “A monoclonal antibody specific for human Thrombospondin-2 has been pre-coated onto a microplate. Standards and samples are pipetted into the wells and any Thrombospondin-2 present is bound by the immobilized antibody. After washing away any unbound substances, an enzyme linked polyclonal antibody specific for human Thrombospondin-2 is added to the wells”). It is understood that capture and detection antibodies in an ELISA must have binding specificity to distinct sites of a target analyte in order to be operable in an ELISA.
With respect to claim 5, Kimura teaches the TSP2 is human TSP2 (see, e.g., p. 507, under “2.1 Patients and clinical examinations”: “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The specificity is evidenced in the package insert for the Quantikine ELISA (see, e.g., p. 11, under “SPECIFICITY”: “This assay recognizes natural and recombinant human Thrombospondin-2”).
With respect to claim 6, Kimura teaches the sample is diluted at a ratio of 1:12 (see, e.g., p. 507, under “2.1 Patients and clinical examinations”: “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The dilution is evidenced in the package insert for the Quantikine ELISA (see, e.g., p. 4, under “SAMPLE PREPARATION”, and p. 6, under “ASSAY PROCEDURE”, steps 3-4).
With respect to claim 10, Kimura teaches advanced liver fibrosis detection with sensitivity greater than 80% and specificity greater than 60% with the circulating levels of TSP2 in the sample greater than 3.6 ng/mL (see, e.g., p. 511, under “TABLE 5”, under “≥F3”).
With respect to claim 11, Kimura teaches wherein advanced liver fibrosis is detected with negative predictive value of about or over 90% (see, e.g., p. 506, under “2.1 Patients and clinical examinations”: “We enrolled 130 biopsy-proven Japanese NAFLD patients”, and p. 507, under “2.1 Patients and clinical examinations”: “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The applicant’s specification discloses that the negative predictive value is typically about or above 90% for the method of claim 1 (see, p. 23, lines 17-21: “Typically, the method detects advanced liver fibrosis with a sensitivity of about or greater than 80%, specificity of about or greater than 60%, and negative predictive value of about or over 90% when the circulating levels of TSP2 in the sample from the subject are greater than about 3.6 ng/ml"). The applicant’s specification also discloses, “Positive and negative predictive values are influenced by the prevalence of disease in the population that is being tested” (see, p. 23, lines 13-14 of the applicant’s specification). Therefore, Kimura teaches wherein advanced liver fibrosis is detected with negative predictive value of about or over 90%.
With respect to claim 12, Kimura teaches the measuring is by immunoassay having a lowest detect limit for TSP2 between about 0.01 ng/mL and about 0.18 ng/mL (see, e.g., p. 507, under “2.1 Patients and clinical examinations”: “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The sensitivity is evidenced in the package insert for the Quantikine ELISA (see, e.g., p. 9, under “SENSITIVITY”: “Ninety-one assays were evaluated and the minimum detectable dose (MDD) of human Thrombospondin-2 ranged from 0.008-0.068 ng/mL”).
With respect to claim 24, Kimura teaches identifying patients needing treatment (see, e.g., p. 506, under “1 Introduction”, col. 1, para. 2: “Fibrosis and NAS are also very relevant for determining treatment response”).
With respect to claim 26, Kimura teaches a kit comprising a set of capture reagents for use in the method of claim 1 (see, e.g., p. 507, under “2.1 Patients and clinical examinations”: “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The Quantikine® ELISA #DTSP20 is a kit (see, e.g., Quantikine® ELISA #DTSP20 package insert, p. 3, under “MATERIALS PROVIDED & STORAGE CONDITIONS”: “Store the unopened kit at 2-8 °C. Do not use past kit expiration date”).
With respect to claim 27, Kimura teaches an immunoassay comprising the capture reagents of claim 2 for use in a method of non-invasively detecting advanced liver fibrosis in a subject with non-alcoholic fatty liver disease (NAFLD), the method comprising: (a) measuring circulating levels of a biomarker thrombospondin 2 (TSP2) in a sample from the subject, and (b) detecting advanced liver fibrosis when the circulating levels of TSP2 in the sample from the subject are greater than about 3.6 ng/ml (see, e.g., p. 507, under “2.1 Patients and clinical examinations”: “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The specificity is evidenced in the package insert for the Quantikine ELISA (see, e.g., p. 11, under “SPECIFICITY”). The statement “This assay recognizes natural and recombinant human Thrombospondin-2” is understood to mean that the assay uses antibodies that are specific for only TSP2.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 8-9 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Kimura (cited above) as evidenced by the package insert for Quantikine® ELISA Human Thrombospondin-2 Immunoassay from R&D Systems by bio-techne, as applied to claims 1-2, 4-6, 10, 12, 24, and 27 above, and further in view of Kwok (“Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study”, published 2016-08, cited in IDS filed 2024-04-09).
Kimura teaches as set forth above, but fails to teach the advanced liver fibrosis is at or above grade F3 as measured by vibration controlled transient elastography (VCTE), wherein grade F3 is graded by liver stiffness measurement cut off value of about 9.6 kilopascal on M probe or 9.3 kilopascal on XL probe, or greater, as in claims 8-9. Kimura fails to teach the subject has NAFLD and type 2 diabetes mellitus, as in claim 13.
However, Kwok teaches the advanced liver fibrosis is at or above grade F3 as measured by vibration controlled transient elastography (VCTE), wherein grade F3 is graded by liver stiffness measurement cut off value of about 9.6 kiloPascal on M probe or 9.3 kPa on XL probe, or greater, as in claims 8-9 (see, e.g., p. 4, col. 1, para. 2). Kwok teaches the subject has NAFLD and type 2 diabetes mellitus, as in claim 13 (see, e.g., p. 1, under”ABSTRACT”, under “Conclusions”).
Kimura and Kwok are analogous to the field of the claimed invention because they are both in the field of liver disease. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the advanced liver fibrosis of Kwok into the assay of Kimura. An artisan would have been motivated to do so because Kwok discloses, “Transient elastrography is a non-invasive test of liver fibrosis that is quick and easy to perform and has a high degree of patient acceptance” (see, e.g., p. 2, col. 1, para. 3). An artisan would have been motivated to use the methods of Kimura on the patients of Kwok because Kwok discloses, “Type 2 diabetes is a major risk factor for NAFLD” (see, p. 1, col. 2, para. 1). An artisan would have had a reasonable expectation of success based on the given disclosures.
Claims 14-15, 17, 19, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Kimura (cited above) as evidenced by the package insert for Quantikine® ELISA Human Thrombospondin-2 Immunoassay from R&D Systems by bio-techne, as applied to claims 1-2, 4-6, 10, 12, 24, and 27 above, and further in view of Yu (“Inflammatory biomarkers and risk of atherosclerotic cardiovascular disease”, published 2018-05-14).
Kimura teaches as set forth above. In addition, Kimura teaches measuring comprises contacting the sample with antibodies having specificity for TSP2 and not to TSP1, TSP3, TSP4, and TSP5, as in claim 17 (see, e.g., p. 507, under “2.1 Patients and clinical examinations”: “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The specificity is evidenced in the package insert for the Quantikine ELISA (see, e.g., p. 11, under “SPECIFICITY”). The statement “This assay recognizes natural and recombinant human Thrombospondin-2” is understood to mean that the assay uses antibodies that are specific for only TSP2.
Kimura teaches measuring comprises contacting the sample with a set of antibodies having a binding specificity to distinct sites of TSP2, as in claim 19 (see, e.g., “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The set of antibodies is evidenced in the package insert for the Quantikine ELISA (see, e.g., p. 2, under “PRINCIPLE OF THE ASSAY”: “A monoclonal antibody specific for human Thrombospondin-2 has been pre-coated onto a microplate. Standards and samples are pipetted into the wells and any Thrombospondin-2 present is bound by the immobilized antibody. After washing away any unbound substances, an enzyme linked polyclonal antibody specific for human Thrombospondin-2 is added to the wells”). It is understood that capture and detection antibodies in an ELISA must have binding specificity to distinct sites of a target analyte in order to be operable in an ELISA.
Kimura teaches the TSP2 is human TSP2, as in claim 20 (see, e.g., p. 507, under “2.1 Patients and clinical examinations”: “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The specificity is evidenced in the package insert for the Quantikine ELISA (see, e.g., p. 11, under “SPECIFICITY”: “This assay recognizes natural and recombinant human Thrombospondin-2”).
Kimura teaches the sample is diluted at a ratio of 1:12, as in claim 21 (see, e.g., p. 507, under “2.1 Patients and clinical examinations”: “Serum TSP1 and TSP2 concentrations were determined using enzyme-linked immunosorbent assays (Quantikine® ELISA, #DTSP10 and #DTSP20, respectively, R&D Systems, Minneapolis, MN)”). The dilution is evidenced in the package insert for the Quantikine ELISA (see, e.g., p. 4, under “SAMPLE PREPARATION”, and p. 6, under “ASSAY PROCEDURE”, steps 3-4).
Kimura fails to teach detecting risk of advanced liver fibrosis per unit increase in the log-transformed circulating level of TSP2 in the sample in ng/mL, wherein the method detects a 2.82 times greater risk of developing advanced liver fibrosis per unit increase in log-transformed circulating levels of TSP2 in the sample, as in claims 14-15. However, Yu teaches the using log-transformed levels of fibrinogen which detects a 2.92 greater risk of developing non-alcoholic fatty liver disease, as in claims 14-15 (see, e.g., p. 208, under “Abstract”, under “Results:”: “Inflammatory marker levels were significantly increased with increasing fatty liver. In multivariate logistic regression analysis adjusted for major confounding factors, the odds ratios of elevated hs-CRP and fibrinogen were significantly higher in participants with mild or moderate-to-severe fatty liver compared to healthy individuals. The cardiovascular risk scores, above cut-off level 10%, were associated with higher levels of inflammatory biomarkers and fatty liver; odds ratio, 3.52 (2.60-4.77) for non-alcoholic fatty liver disease with hs-CRP, and 2.92 (2.12-4.00) for non-alcoholic fatty liver disease with fibrinogen”).
Kimura and Yu are analogous to the field of the claimed invention because they are both in the field of liver disease. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the log-transform and risk multiplier of Yu on the relationship between TSP2 and advanced liver fibrosis of Kimura. An artisan would have been using applying the known technique of Yu (log-transforming biomarker levels to analyze the relationship between a biomarker and the risk of a disease) to known method of Kimura (measuring TSP2 to predict the risk of advanced liver fibrosis). The result would have been a predictable relationship between TSP2 and the risk of advanced liver fibrosis. An artisan would have had a reasonable expectation of success based on the given disclosures.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Kimura (cited above) as evidenced by the package insert for Quantikine® ELISA Human Thrombospondin-2 Immunoassay from R&D Systems by bio-techne and Yu (cited above), as applied to claim 14-15, 17, 19, and 20-21, and further in view of Adams (“Biomarkers of liver fibrosis”, published 2011).
Kimura and Yu teach as set forth above, but fail to teach detecting the risk of developing advanced liver fibrosis is for risk within a period between about 0.1 years and about 3 years from measuring TSP2, as in claim 16.
However, Adams teaches the prediction of liver fibrosis following patients for 4 years, as in claim 16 (see, e.g., p. 805, col. 1, para. 5).
Kimura, Yu, and Adams are analogous to the field of the claimed invention because they are all in the field of liver disease. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the methods of Kimura as modified by Yu to predict liver fibrosis over a period of years as in Adams. An artisan would have been motivated to do so because Adams discloses, “Fibrosis prediction is an essential part of the assessment and management of patients with chronic liver disease” (see, p. 802, under “Abstract”). An artisan would have had a reasonable expectation of success based on the given disclosures.
While Adams does not explicitly teach prediction over a period between 0.1 years and 3 years from measuring, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to perform routine optimization of the components in the claimed invention to make and use the claimed invention. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Routine optimization is not considered inventive and no evidence has been presented that arriving at the claimed prediction period was anything other than routine, that the properties of the prediction period from the optimization has any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art. Optimization of parameters is a routine practice that would be obvious for the artisan to employ. See MPEP § 2144.05. The artisan would have had a reasonable expectation of success based on the cumulative disclosure of Kimura, Yu, and Adams.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over over Kimura (cited above) as evidenced by the package insert for Quantikine® ELISA Human Thrombospondin-2 Immunoassay from R&D Systems by bio-techne and Yu (cited above), as applied to claim 14-15, 17, 19, and 20-21, and further in view of Kwok (cited above).
Kimura and Yu fail to teach the subject has NAFLD and type 2 diabetes mellitus, as in claim 23.
However, Kwok teaches the subject has NAFLD and type 2 diabetes mellitus, as in claim 23 (see, e.g., p. 1, under”ABSTRACT”, under “Conclusions”).
Kimura, Yu, and Kwok are analogous to the field of the claimed invention because they are both in the field of liver disease. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the patients of Kwok into the methods of Kimura. An artisan would have been motivated to use the methods of Kimura on the patients of Kwok because Kwok discloses, “Type 2 diabetes is a major risk factor for NAFLD” (see, p. 1, col. 2, para. 1). An artisan would have had a reasonable expectation of success based on the given disclosures.
Conclusion
No claims are allowed.
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/MICHAEL CAMERON SVEIVEN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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