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 .
Response to Amendment
Applicant’s amendment filed 04/28/2026 is acknowledged. Claim 10 is amended and claims 11-13 are new. Claims 1-5 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
In the response to the Restriction requirement filed 03/31/2025, Applicant provisionally elected the species of ANXA3, TGOLN2, F10 and HEXB. In the Office action mailed 05/07/2025, the examiner extended the search to include A2M. In response to Applicant’s amendment filed 08/07/2025, the examiner extended the search to include Tenascin C (TNC) in the Office action mailed 10/16/2025. In response to Applicant’s amendment filed 01/06/2026, the examiner extended to include Fetuin B (FETUB) and Lipocalin 2 (LCN2) in the Office action mailed 02/10/2026. In the amendment filed 04/28/2026, Applicant has deleted reference to FETUB and LCN2 in claim 10, thus the search is being extended herein to include Apolipoprotein M (APOM) along with the originally elected Annexin A3 (ANXA3) and coagulation factor X (F10).
Claims 10-13 are under examination.
Claim Interpretation
The Office action mailed 02/10/2026 stated that claim 10 did not recite a judicial exception. Upon further consideration this statement is withdrawn. The MPEP 2106.04 (II)(A)(1) Step 2A, Prong One states examiners must evaluate whether the claim recites a judicial exception, i.e. whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim. While the terms “set forth” and “described” are both equated with “recite”, their different language is intended to indicate that there are two ways in which an exception can be recited in a claim. For instance, the claims in Diehr, 450 U.S. at 178 n. 2, 179 n.5, 191-92, 209 USPQ at 4-5 (1981), clearly stated a mathematical equation in the repetitively calculating step, and the claims in Mayo, 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012), clearly stated laws of nature in the wherein clause, such that the claims “set forth” an identifiable judicial exception. Alternatively, the claims in Alice Corp., 573 U.S. at 218, 110 USPQ2d at 1982, described the concept of intermediated settlement without ever explicitly using the words “intermediated” or “settlement.”
In the instant case the claims describe a judicial exception because the preamble is relaying that the biomarkers to be measured are associated with diagnosis of preeclampsia. In the method steps of the claim the artisan is measuring said biomarkers. Once the claim is practiced, it appears the artisan has accomplished the task set forth in the preamble, even though there is no “wherein” clause stating that the presence of the biomarkers is correlated to preeclampsia or there is no explicit diagnosis step.
This interpretation is further supported by Applicant’s arguments at pages 5-6 of the Remarks filed 04/28/2026, asserting the prior art “describes the biomarkers only as biomarkers for kidney injury, and that preeclampsia is mentioned therein merely as a background risk factor or clinical sign rather than the target condition for diagnosis… [and there] is no suggestion and nexus in the prior art that F10 can be considered as a biomarker for diagnosing preeclampsia”. Therefore, the phrase “associated with diagnosis of pre-eclampsia” describes a judicial exception of diagnosis.
Since the interpretation necessitates the raising of new issues, this rejection is being made non-final in order to give Applicant the opportunity to respond.
Rejections Withdrawn
Claim Rejections - 35 USC § 102
The following rejections under 35 U.S.C. 102(a)(1) are withdrawn in response to Applicant’s amendment of claim 10 to delete reference to fetuin B.
Claim 10 as being anticipated by Tarca et al. (WO 2013/188686); and
Claim 10 as being anticipated by Than et al. (EP 3339861).
The rejection of claim 10 under 35 U.S.C. 102(a)(1) as being anticipated by Stepan et al. (J. Endocrinol. Invest. 33: 629-632, 2010) is withdrawn in response to Applicant’s amendment of claim 10 to delete reference to lipocalin 2.
New Rejections/Rejection Maintained
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 10-13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claims recite methods of detecting biomarkers associated with diagnosis of preeclampsia in a subject. Thus, the claims are drawn to the statutory category of a process. See Step 1 of the Revised Guidelines.
The first step in determining whether a claim recites patent eligible subject matter is to consider whether the claims recite an abstract idea, law of nature or a natural phenomenon. See Prong One of Step 2A of the Revised Guidelines. The claims recite detecting biomarkers associated with preeclampsia in a blood sample of subject comprising detecting whether at least one of the recited biomarkers are present in the sample by contacting the sample with an antibody or an antigen-binding fragment thereof that specifically binds the biomarker. The claims recite the following biomarkers:
Claim
Biomarkers
10
Annexin A3 (ANXA3) Apolipoprotein M (APOM), Quiescin sulfhydryl oxidase 1 (QSOX1), coagulation factor X (F10), Serpin Family A member 11 (SERPINA1 1), Proteoglycan 2 (PRG2), Sex hormone binding globulin (SHBG), Hemoglobin subunit delta (HBD), ceruloplasmin (CP), and Serpin Family A member 4 (SERPINA4)
11*
Alpha-2-Macroglobulin (A2M), Apolipoprotein B (APOB), Pregnancy Zone Protein (PZP), Fetuin B (FETUB), Fibronectin 1 (FN1), Lipocalin 2 (LCN2), Trans-Golgi Network Protein 2 (TGOLN2), Tenascin C (TNC), Angiotensinogen (AGT), Hexosaminidase Subunit Beta (HEXB), and Von Willebrand Factor (VWF)
12
Annexin A3 (ANXA3) and Apolipoprotein M (APOM)
13**
Serpin Family A member 11 (SERPINA1 1), Proteoglycan 2 (PRG2), Sex hormone binding globulin (SHBG), Quiescin sulfhydryl oxidase 1 (QSOX1), coagulation factor X (F10), Hemoglobin subunit delta (HBD), ceruloplasmin (CP), Serpin Family A member 4 (SERPINA4), Alpha-2-Macroglobulin (A2M), Apolipoprotein B (APOB), Pregnancy Zone Protein (PZP), Fetuin B (FETUB), Fibronectin 1 (FN1), Lipocalin 2 (LCN2), Trans-Golgi Network Protein 2 (TGOLN2), Tenascin C (TNC), Angiotensinogen (AGT), Hexosaminidase Subunit Beta (HEXB), and Von Willebrand Factor (VWF)
*Depends from claim 10
**Depends from claim 12
As noted under “Claim Interpretation”, the preamble phrase “detecting biomarkers associated with diagnosis of preeclampsia” describes diagnosis, and is therefore a judicial exception. The instant claims inherently encompass a relationship between protein expression levels of the recited biomarkers and diagnosis of preeclampsia.
The judicial exception relies upon the correlation between the presence of the recited protein biomarker levels in the sample and diagnosis of preeclampsia, which inherently requires the mental step of comparing biomarker levels. The mental step of comparing biomarker levels is similar to comparing information regarding a sample or test subject to a control or target data (see Univ. of Utah Research Found, v. Ambry Genetics Corp., 113 USPQ2d 1241 (Fed. Cir. 2014), or diagnosing an abnormal condition by performing clinical tests and thinking about the results (see In re Grams, 12 USPQ2d 1824 (Fed. Cir. 1989). The answer to Prong One of Step 2A is yes.
The second step in determining patent eligibility of the claimed subject matter is to consider whether the claims recite additional elements that integrate the judicial exception into a practical application. See Prong Two of Step 2A of the Revised Guidelines. The claims all recite detection of biomarkers. The judicial exceptions are not integrated into a practical application because measuring biomarkers is merely the necessary data gathering step required in order to perform the mental analysis step of diagnosis. The discovery of the relationship between biomarkers and a particular condition is not sufficient to integrate the judicial exception into a practical application. See MPEP 2106.04(I), which instructs:
The Supreme Court’s cited rationale for considering even “just discovered” judicial exceptions as exceptions stems from the concern that “without this exception, there would be considerable danger that the grant of patents would ‘tie up’ the use of such tools and thereby ‘inhibit future innovation premised upon them.’” Myriad, 569 U.S. at 589, 106 USPQ2d at 1978-79 (quoting Mayo, 566 U.S. at 86, 101 USPQ2d at 1971). See also Myriad, 569 U.S. at 591, 106 USPQ2d at 1979 (“Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the §101 inquiry.”). The Federal Circuit has also applied this principle, for example, when holding a concept of using advertising as an exchange or currency to be an abstract idea, despite the patentee’s arguments that the concept was “new”. Ultramercial, Inc. v. Hulu, LLC, 772 F.3d 709, 714-15, 112 USPQ2d 1750, 1753-54 (Fed. Cir. 2014). Cf. Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1151, 120 USPQ2d 1473, 1483 (Fed. Cir. 2016) (“a new abstract idea is still an abstract idea”) (emphasis in original).
Further, in explaining Prong Two of Step 2A, MPEP 2104.04(II)(A)(2) states patent “eligibility ‘cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself’”. In summary, the judicial exception is not integrated into a practical application because the additional steps constitute mere data gathering. The answer to Prong Two of Step 2A is no.
The final step in determining whether the claims recite patent eligible subject matter is to consider whether they recite additional elements that amount to significantly more than the judicial exceptions. The claims do not include any additional elements that are sufficient to amount to significantly more than the judicial exception because biomarker detection assays are well-known, routine and conventional to one skilled in the art at the time of the filing of the invention. For instance, Liu et al. (BMC Medicine, 2013; 11: 236—of record) teaches both a protein chip technology assay and ELISA for measuring various biomarkers in patients with preeclampsia (see p. 3, Figure 1, also left column). In addition, Vaiman (US2020209260—of record) teach that immunoassays were routine in the art (paragraph [0029]):
Methods for performing immunological analysis are well known to those skilled in the art, for example the ELISA method (enzyme-linked immunosorbent assay), the IRMA method (immunoradiometric assay), mass spectrometry, chromatography or the RIA method (radioimmunoassay).
The detecting step is simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality to the judicial exceptions (see MPEP 2106.05(d)).
Thus, the claims do not recite patent eligible subject matter.
Claim Rejections - 35 USC § 112(a)
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 10-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for providing information on diagnosis of preeclampsia, the method comprising measuring at least one protein selected from the group consisting of ANXA3, A2M, APOB, PZP, FETUB, FN1, LCN2, APOM, QSOX1, TGOLN2, F10, SERPINA11, PRG2, SHBG, TNC, HBD, AGT, CP, HEXB, SERPINA4, and VWF, wherein an increase in ANXA3, A2M, APOB, PZP, FETUB, FN1, LCN2, APOM, QSOX1, TGOLN2, F10, SERPINA11, PRG2, SHBG and TNC protein levels or a decrease in HBD, AGT, CP, HEXB, SERPINA4, and VWF protein levels compared to control indicates the patient has preeclampsia, or alternatively, diagnostic methods as disclosed in the prior art, does not reasonably provide enablement for the claims as broadly recited. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” (See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 Fed. Cir. 1988). These factors include, but are not limited to: (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
As noted above, claims 10-13 are interpreted as reading upon diagnosis based upon detection of the preeclampsia associated biomarkers. The claims do not recite whether the proteins are up- or down-regulated in order to provide information on diagnosis of preeclampsia. The specification teaches that in patients with preeclampsia, “15 proteins showed a significant increase (ANXA3, A2M, APOB, PZP, FETUB, FN1, LCN2, APOM, QSOX1, TGOLN2, F10, SERPINA11, PRG2, SHBG and TNC) and 6 proteins showed a significant decrease (HBD, AGT, CP, HEXB, SERPINA4, and VWF)” when compared to control (see paragraph bridging pages 9-10). The prior art of Nagalla et al. (WO2009097584—of record) teach that A2M is decreased and VWF is increased compared to controls at 9-11 weeks (see p. 36, Table 4a), while VWF is decreased compared to control at 10-14 weeks (see p. 37, Table 4b). Blumenstein et al. (WO2009108073—of record) teach a higher level of angiotensinogen (AGT) is indicative of a risk of developing preeclampsia (see claims 1 and 8), whereas the instant specification teaches AGT levels are lower in preeclampsia. The differences in results between the prior art and the instant specification suggests that there is a lack of predictability regarding whether the recited proteins are increased or decreased in preeclampsia, and that timing of sample collection and measurement assays may affect results. The instant specification also notes that a commercial kit for preeclampsia diagnosis comprising measuring a protein biomarker has a low detection rate (see p. 1).
Due to the large quantity of experimentation necessary to determine how the expression levels of the recited protein biomarkers change when diagnosing preeclampsia, the contradictory state of the prior art, which underscores the unpredictability of biomarker expression to diagnose disease, and the breadth of the claims which fail to recite limitations on whether the recited protein levels are up or down regulated, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Notice for all US Patent Applications filed on or after March 16, 2013: In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 10-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Blumenstein et al. (WO2009108073—of record). This rejection was necessitated by Applicant’s amendment. Blumenstein et al. teach a method for predicting the risk of a female subject developing preeclampsia comprising observing and detecting the level of one or more proteins, wherein the one or more proteins is chosen from Apolipoprotein M (APOM), alpha-2-macroglobulin (A2M), pregnancy zone protein (PZP) and fibronectin 1 (FN1), among others, wherein a higher level of A2M, PZP and FN1 and a lower level of APOM compared to control is indicative of a risk of developing preeclampsia (see claims 1, 5, 8 and 9). Further, Blumenstein et al. teach that the biomarkers s may be measured by ELISA and the sample is a blood sample (see claims 54-55) Thus, Blumenstein et al. teach the limitations of claims 10-13.
The rejection of claim 10 under 35 U.S.C. 102(a)1) as being anticipated by Anderberg et al. (US 20160003850) is maintained for reasons of record and the following.
Response to Arguments
Applicant argues at pages 5-6 of the Remarks filed 04/28/2026 that Anderberg et al. “describes the biomarkers only as biomarkers for kidney injury, and that preeclampsia is mentioned therein merely as a background risk factor or clinical sign rather than the target condition for diagnosis…[and there] is no suggestion and nexus in the prior art that F10 can be considered as a biomarker for diagnosing preeclampsia”.
This argument has been fully considered, but is not found persuasive. Claim 10 is interpreted as detecting biomarkers associated with diagnosis of pre-eclampsia in a subject. Anderberg et al. explicitly disclose that patients with preeclampsia are at risk for kidney injury: “the subject is selected for risk stratification based on the preexistence in the subject of one or more known risk factors for prerenal, intrinsic renal, or postrenal ARF…[for] example…preeclampsia” (see paragraph [0023]). Anderberg et al. also explicitly teach that their kidney marker assay is not interpreted in isolation, but rather also in combination with variables indicating risk factors for conditions such as preeclampsia (see paragraphs [0043]; [0109]; claim 11). Therefore, it flows therefrom that Anderberg et al. teach F10 is biomarker associated with the diagnosis of pre-eclampsia.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Kim et al. (Proteomics 2016, 16, 1581-1589) teach that APOM was downregulated in patients with preeclampsia and hypertension during pregnancy (see p. 1584, right column, last paragraph). In addition, Nagalla et al. (WO2009097584—of record) teach a method for the diagnosis of pre-eclampsia in a female mammalian subject in early gestation comprising testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of alpha-2-macroglobulin (A2M), apolipoprotein B (APOB), fibronectin (FN1) and von Willebrand factor (VWF), among others, and diagnosing the subject with preeclampsia if there is a difference in expression compared to normal maternal serum (see claims 1, 30). Nagalla et al. teach VWF is decreased in preeclampsia compared to control at 10-14 weeks (see p. 37, Table 4b) and that FN1 is increased in preeclampsia compared to control at 9-11 weeks (see p. 36, Table 4a; also, p. 46). Tarca et al. (WO 2013/188686—of record) teach determining levels of the biomarker, fetuin B (FETUB), among others, in a biological sample obtained from a female, wherein the sample is blood (see claims 1-5). Finally, Than et al. (EP 3339861—of record) determining levels of the biomarker, fetuin B, among others, in a biological sample, wherein the biological sample obtained from a female, wherein the biological sample is blood (see claims 1-4 and 6).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M BORGEEST whose telephone number is (571)272-4482. The examiner can normally be reached M-F 9-5:30 EDT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 5712720911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675
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