DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Restriction to one of the following inventions is required under 35 U.S.C. 121:
I. Claims 1-12 and 14-19, drawn to an in vitro method for assessing cholangiocarcinoma in a patient sample comprising determining the level of tissue inhibitor of metalloptoteinase-1 (TIMP1) in said sample, comparing the level of TIMP1 with a reference level of TIMP1 and assessing cholangiocarcinoma, wherein an increased level of TIMP1 compared to the reference level of TIMP1 is indicative for cholangiocarcinoma in the patient sample, classified in G01N 2470/04.
II. Claims 13 and 20, drawn to a kit comprising antibodies or fragments thereof required to determine a level of TIMP1 and a level of matrix metalloproteinase-2 (MMP2) in a patient sample, classified in G01N 2333/96494.
3. The inventions are independent or distinct, each from the other because:
Inventions II and I are related as product and process of use, respectively. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case, the antibodies of kit II can be implemented in the in vitro assay of Group I or as an immunotherapeutic agent within an in vivo treatment regimen.
4. Restriction for examination purposes as indicated is proper because all the inventions listed in this action are independent or distinct for the reasons given above and there would be a serious search and/or examination burden if restriction were not required because one or more of the following reasons apply:
• the inventions have acquired a separate status in the art in view of their different classification.
• the inventions have acquired a separate status in the art due to their recognized divergent subject matter.
• the inventions require a different field of search (e.g., searching different classes/subclasses or electronic resources, or employing different search strategies or search queries).
Applicant is advised that the reply to this requirement to be complete must include (i) an election of an invention to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected invention.
The election of an invention may be made with or without traverse. To reserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the restriction requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the Examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
5. This application contains claims directed to the following patentably distinct species (detected molecule): a. nucleic acid; and b. protein. The species are independent or distinct because each molecule is different structure and composition. In addition, these species are not obvious variants of each other based on the current record.
Applicant is required under 35 U.S.C. 121 to elect a single disclosed species, or a single grouping of patentably indistinct species, for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable. Currently, claims 1 and 6 are generic.
There is a serious search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply:
• the inventions have acquired a separate status in the art in view of their different classification.
• the inventions have acquired a separate status in the art due to their recognized divergent subject matter.
• the inventions require a different field of search (e.g., searching different classes/subclasses or electronic resources, or employing different search strategies or search queries).
Applicant is advised that the reply to this requirement to be complete must include (i) an election of a species to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected species or grouping of patentably indistinct species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered nonresponsive unless accompanied by an election.
The election may be made with or without traverse. To preserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the election of species requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable on the elected species or grouping of patentably indistinct species.
Should applicant traverse on the ground that the species, or groupings of patentably indistinct species from which election is required, are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing them to be obvious variants or clearly admit on the record that this is the case. In either instance, if the Examiner finds one of the species unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other species.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which depend from or otherwise require all the limitations of an allowable generic claim as provided by 37 CFR 1.141.
6. During a telephone conversation with Ryan P. Hiler on February 27, 2026 a provisional election was made without traverse to prosecute the invention of Group 1, claims 1-12 and 14-19. Affirmation of this election must be made by applicant in replying to this Office action. Claims 13 and 20 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
7. Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
8. The Examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the Examiner before the patent issues. See MPEP § 804.01.
Claim Objection
9. Claim 6 is objected to because of the following informality: the acronym should be accompanied by the full-term cholangiocarcinoma on line 1. Applicant should cite “cholangiocarcinoma (CCA)” on line 1.
Correction is required.
Claim Rejections - 35 USC § 112
10. 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.
11. Claims 1-5, 8, 11, 12 and 14-19 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.
a. Claims 2, 3, 7 and 19 recite either, “an antibody or fragment thereof”. “The underlined phrase is vague and indefinite since it is not clear what part of the antibody should bind its target. Applicant can obviate the instant rejection deleting “fragment thereof” and replacing with “antigen-binding fragment thereof” or “antibody-binding fragment thereof”.
b. Claims 1 and 11 read on methods for assessing cholangiocarcinoma (CAA) comprising detection of level(s) of tissue inhibitor of metalloproteinase-1 (TIMP-1) and/or matrix metalloproteinase-2 (MMP2) in a patient sample and reference sample with antibodies or antigen-binding fragments and comparing the levels between the two samples, wherein an increased level of TIMP1 and/or presence of matrix metalloproteinase-2 (MMP2) is indicative of cholangiocarcinoma (CCA). However, it is not clear what is the discriminating level or presence that aids one of ordinary skill in the art to differentiate between cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC).
Likewise, claim 8 reads on a method for assessing CAA comprising determining levels of TIMP1, step (a’) and MMP2, step (b’) in a patient sample into a statistical methodology to produce an output value indicative for CCA diagnosis or risk of developing CCA. However, it is not clear what the output value should be to clarify between a clear CCA diagnosis or the risk of developing CCA.
Accordingly, the metes and bounds cannot be determined.
Claim Rejections - 35 USC § 101
12. 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.
13. The claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claim(s) 1-12 and 14-19 is/are directed to a judicial exception.
Claims 1-12 and 14-19 are drawn to a non-statutory method having a "natural principle" as a limiting element or step without reciting additional elements/steps that integrate the natural principle into the claimed invention such that the natural principle is practically applied, and are sufficient to ensure that the claim amounts to significantly more than the natural principle itself.
In the instant case, the "natural principle" is: detection of level(s) of tissue inhibitor of metalloproteinase-1 (TIMP-1) and/or matrix metalloproteinase-2 (MMP2) in a patient sample and reference sample with antibodies or antigen-binding fragments and comparing levels between the two samples, wherein an increased level of TIMP1 and presence of matrix metalloproteinase-2 (MMP2) is indicative of cholangiocarcinoma (CCA), at risk of developing CCA and/or differentiates CCA from hepatocellular carcinoma (HCC).
The analysis as set forth in the 2019 Guidance is as follows:
Step 1: Yes, claims are drawn to a method which is one of the four statutory categories, a process.
Step 2A, prong 1: Yes, the claims recite/describe/set forth a judicial exception. The claims describe the relationship between the presence and/or level of TIMP2 and/or MMP2 in a patient’s sample is indicative of the patient has CCA, at risk of developing CCA and/or differentiates CCA from hepatocellular carcinoma (HCC).
Step 2A, prong 2: No, the judicial exception is not integrated into a practical application. The claims do not rely on or use the exception here. Once the presence and/or level of TIMP2 and/or MMP2 is detected in the patient’s sample by conventional means, i.e. implementing antibodies, there are no additional elements or combination of additional elements to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Step 2B: There is no inventive concept present in the clams. The steps of analyzing the presence of biomarker(s) or more specifically TIMP1 and/or MMP2 in a biological sample is established by well understood, routine conventional methods, i.e. data gathering necessary to perform the correlation. The claims and the steps within inform one of ordinary skilled in the art the level and/or presence of one or two biomarkers within a patient’s biological sample identifies an individual as affected with CCA, at risk of CCA, and/or differentiates CCA from HCC. The claims do not recite additional elements that amount to significantly more than the judicial exception.
The claim(s) recite(s) detecting TIMP1 and/or MMP2 from a patient’s sample with antibodies to arrive at a CCA diagnosis. In regard to Step 2B, this judicial exception is not integrated into a practical application because the additional elements and do not add a meaningful limitation to the method because they amount to simply implementing the method using standard immunological techniques. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Moreover, the statistical methodology to produce an output value performed by a computing device and calculated level values and multivariate scores utilizing algorithms in the claims are regarded as abstract ideas. These are calculations implemented with a mathematical algorithm. These processes are not unpatentable simply because it contains a mathematical algorithm, the claims as a whole have been analyzed and determined to not contain additional elements or provide significantly more than the natural laws. Accordingly, these claims are not be eligible under step 2A or step 2B.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because assaying for candidate cancer biomarkers and making clinical decisions based on the presence of said biomarkers is routine in the art. This does not add significantly more and is not an inventive concept. Methods for making such determinations were well known in the art, these steps simply tell researchers to engage in well-understood, routine, conventional activity previously engaged in by scientists in the field. Such activities are normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such law. Detection of complexes comprising candidate cancer biomarkers and binding agents has been observed by applicant but not engineered by applicant. The claims do not add significantly more to the natural phenomenon because the claims do not require a novel reagent, apparatus of incorporate a novel treatment based on the correlation.
A claim that focuses on use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, and added something significant to, the natural principle itself. See Mayo, 101 USPQ2d at 1966. Recited elements such as “determining”, “comparing”, “assessing”, “quantifying” and “providing” based on the natural principle impose no meaningful limit on the performance of the claimed invention. Likewise, as well as equations and formulas based on the natural principle impose no meaningful limit on the performance of the claimed invention.
As set forth the claims do not impose meaningful limits on the performance of the claimed invention.
Patents cannot be obtained on subject matter identified by the courts as being exempted from eligibility (i.e., laws of nature, natural phenomenon, and abstract ideas). Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the recited natural principle. The claims do not "practically apply" the natural principle; rather, the claims "simply inform" the natural principle to one performing routine active method steps and do not amount to significantly more than the natural principle itself. Thus, the technology used by the instant claims is well-known in the art and does not contribute significantly more to the judicial exception. See the 2019 Revised Patent Subject Matter Eligibility Guidance and Federal Register https://www.federalregister.gov/documents/2019/10/18/2019-22782/october-2019-patent-eligibility-guidance-update; and FDsys.gov.
Claim Rejections - 35 USC § 102
14. 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.
15. Claim(s) 1-5, 11, 12, 14 and 15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al., (Cancer Management and Research 10675-10681, published online 23 December 2019/ IDS reference #2 submitted March 14, 2025), as evidenced by Boster Biological Technology Co. Ltd. (Package insert, 11 pages and product info, 6 pages, printed February 2026) and IBM SPSS Statistics Base 17.0 User’s Guide [Computer software]. IBM Corp. 640 pages (2007).
Zhang discloses detecting tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in the peripheral blood and serum of cancer patients and healthy volunteers as a control group, see page 10676, Patients segment. The expression level of the biomarker was higher than in the cancer patients (particularly the preoperative patients) than the control, see Figure 1 on page 10678.
Figure 2 on page 10679 shows brighter bands of mRNA fragment of TIMP-1 from the preoperative cancer patients (lane 5) than the control group (lane 2), thereby reading on increased mRNA levels of the said biomarker. Therefore, both Figures evidence the detected levels are indicative for cholangiocarcinoma (CCA) and distinguishes CCA from hepatocellular carcinoma (HCC) and from risk of the additional disorders and diseases listed in claim 12.
The level of TIMP-1 in the serum of the cancer patients were detecting using the enzyme-linked immunosorbent assay (ELISA) method, see page 10676, 1st column (col.), lines 5-8; and Levels…segment on page 10676. “The expression of … TIMP-1 in the serum was detected using the double sandwich ELISA method according to the instructions provided by the manufacturer [Boster].”, see page 10676, 2nd col., lines 2-5.
As evidenced by Boster product info, “[t]he capture antibody is monoclonal antibody from mouse and the detection antibody is polyclonal antibody from goat.”, see page 2. Quantifiable signals are observed and calculated with the implementation of the biotinylated antibody, avidin-biotin-peroxidase (ABC) and substrate solution provided by Boster, see Boster product info, pages 2 and 3; and Boster package insert, page 2.
It is within the purview of the Examiner, differences in levels are “calculated” in the mind of the of the person of ordinary skill in the art when viewing the differences in brightness between the biomarker and the control, as well as viewing the ratio of levels noted in Figure 1 on page 10678. Notwithstanding, statistical analyses is performed on all data utilizing a computing device, see page 10676, 2nd col., Statistical Analyses segment. As evidenced by IBM SSPP…User’s guide the statistical methodology includes linear statistical models, quadratic model, discriminant analysis classification, nonparametric tests, logistic regression, clinical variables (gender, age), and multivariate models, see the entire guide and in particular, pages iii, 73, 120, 121, 164, 166, 174-176, 271, 275, 276, 280, 296, 300, 304, 307-308, 310, 320, 325, 326, 329, 343, 353, 359, 361, 368, 387, 390, 392-395, 398, 404, 422-440, 463, 465, 467 and 475.
16. Claim(s) 6-10 and 16-19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al., (Cancer Management and Research 10675-10681, published online 23 December 2019/ IDS reference #2 submitted March 14, 2025), as evidenced by Boster Biological Technology Co. Ltd. (Package insert, 11 pages and product info, 6 pages, printed February 2026) and IBM SPSS Statistics Base 17.0 User’s Guide [Computer software]. IBM Corp. 640 pages (2007).
Zhang discloses detecting tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and matrix metalloproteinase-2 (MMP2) in the peripheral blood and serum of cancer patients and healthy volunteers as a control group, see page 10676, Patients segment. The expression levels of both biomarkers were higher than in the cancer patients (particularly the preoperative patients) than the control, see Figure 1 on page 10678.
Figure 2 on page 10679 shows brighter bands of mRNA fragment of MMP-2 and TIMP-1 from the preoperative cancer patients (lane 5) than the control group (lane 2), thereby reading on increased mRNA levels of the said biomarkers. Therefore, both Figures evidence the detected levels are indicative for cholangiocarcinoma (CCA) and distinguishes CCA from hepatocellular carcinoma (HCC) and from risk of the additional disorders and diseases listed in claim 12.
The levels of MMP-2 and TIMP-1 in the serum of the cancer patients were detecting using the enzyme-linked immunosorbent assay (ELISA) method, see page 10676, 1st column (col.), lines 5-8; and Levels…segment on page 10676. “The expression of MMP-1… and TIMP-1 in the serum was detected using the double sandwich ELISA method according to the instructions provided by the manufacturer [Boster].”, see page 10676, 2nd col., lines 2-5.
As evidenced by Boster product info, “[t]he capture antibody is monoclonal antibody from mouse and the detection antibody is polyclonal antibody from goat.”, see page 2. Quantifiable signals are observed and calculated with the implementation of the biotinylated antibody, avidin-biotin-peroxidase (ABC) and substrate solution provided by Boster, see Boster product info, pages 2 and 3; and Boster package insert, page 2.
It is within the purview of the Examiner, differences in levels are “calculated” in the mind of the of the person of ordinary skill in the art when viewing the differences in brightness between the biomarkers and the control, as well as viewing the ratio of levels noted in Figure 1 on page 10678. Notwithstanding, statistical analyses is performed on all data utilizing a computing device, see page 10676, 2nd col., Statistical Analyses segment. As evidenced by IBM SSPP…User’s guide the statistical methodology includes linear statistical models, quadratic model, discriminant analysis classification, nonparametric tests, logistic regression, clinical variables (gender, age), and multivariate models, see the entire guide and in particular, pages iii, 73, 120, 121, 164, 166, 174-176, 271, 275, 276, 280, 296, 300, 304, 307-308, 310, 320, 325, 326, 329, 343, 353, 359, 361, 368, 387, 390, 392-395, 398, 404, 422-440, 463, 465, 467 and 475.
Conclusion
17. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM, Monday through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
24 February 2026
/Alana Harris Dent/ Primary Examiner, Art Unit 1643