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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/12/25 has been entered.
Claims 1, 2, 8-11, 14, 15, 17-26, and 28-30 are pending and currently under consideration.
Rejections Maintained
Claim Rejections - 35 USC § 101
Claims 1, 2, 8-11, 14, 15, 17-26, and 28-30 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. Abstract ideas include mathematical concepts (including mathematical relationships, formulas, equations, and calculations), mental processes (including concepts performed in the human mind), and certain methods of organizing human activity (including managing personal behavior, relationships, or interactions between people). The rationale for this determination is explained below:
Claims 1, 2, 8-11, 14, 15, 17-26, and 28-30 are directed to abstract ideas and natural phenomenon because the claims recite natural phenomenon and abstract ideas (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” include: levels of cell free nucleosomes in plasma correlate with (i) vascular and haematological cancer diagnosis and (ii) efficacy of therapy in a subject. The “abstract ideas” (all mental processes) include: (i) the “using” step of claim 1, (ii) the “comparing” step of claim 14, and (iii) the “using” step of claim 29. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (when considered both individually and as an ordered combination) are limited to well-understood, routine and conventional limitations of contacting plasma samples from a subject with binding agents known to detect, measure, and/or characterize cell free nucleosomes and optionally measure protein such as an interleukin (“Step 2B”). Methods of contacting plasma samples from a subject with binding agents to detect, measure, and/or characterize cell free nucleosomes and optionally measure protein such as an interleukin are well-understood, routine and conventional in the art (see above cited teachings of Micallef et al (WO 2016/067029 A1; 5/6/16; 9/16/22 IDS) and teachings of Mueller et al (BMC Cancer, 2006, 6(143): 1-10), in particular). Well-understood, routine and conventional limitations are not meaningful limitations and are not enough to qualify the claimed method as reciting something “significantly more” than the judicial exception(s) (see Part I.B.1 of the interim Guidance).
MPEP 2106.05(d)(II) provides a non-limiting list of laboratory techniques recognized by courts as well-understood, routine, conventional activity. These techniques include:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
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Further, the specification acknowledges methods encompassed by the claims using ELISA (which is a technique that contacts plasma samples from a subject with binding agents to detect, measure, and/or characterize cell free nucleosomes) are well known in the art (see “The immunoassays described herein…ELISA…All of said immunoassay methods are well known in the art…” at paragraph spanning pages 16-17, in particular). Here, the claims do not contain any significant additional elements or steps beyond the observation of judicial exception(s) present when performing routine and conventional methods. 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 judicial exception(s). Further, just as methods comprising detecting paternal DNA sequences in particular samples by PCR was identified in Ariosa v. Sequenom as "well-known, routine, and conventional" (see first paragraph on page 13 of Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015)) even though the prior art did not demonstrate detecting said paternal DNA sequences in said particular samples by PCR, the methods encompassed by the instant claims are well-known, routine, and conventional. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (common methods of detecting nucleosomes) are routinely performed in the art to obtain data regarding presence of nucleosomes. In regards to “diagnosing", it is further noted that merely presenting results of a process otherwise unpatentable under 35 U.S.C. 101 is insufficient to establish eligibility under the statute. See FairWarning IP, LLC v. Iatric Sys., Inc., No. 2015-1985, 2016 WL 5899185, at *3 (Fed. Cir. Oct. 11, 2016) (claim unpatentable under 35 U.S.C. 101 despite recitation of the step: “providing notification if [an] event has occurred”). Moreover, “[w]hile preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility…." Ariosa Diagnostics, Inc., v. Sequenom, Inc., 788 F.3d 1371, 1379 (Fed. Cir. 2015), cert. denied, No. 15-1182, 2016 WL 1117246 (U.S. June 27, 2016). Further, “Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the § 101 inquiry.” Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2117 (2013). The claims do not recite something “significantly more” than the judicial exception(s); rather, the claims “simply inform” the natural phenomenon to one performing routine active method steps and do not amount to significantly more than the judicial exception(s).
Response to Arguments
In the Reply of 12/12/25, Applicant repeats arguments previously addressed in the Advisory Action of 10/16/25. Applicant further argues one of ordinary skill in the art would not have regarded using non-human mammalian samples as routine or conventional due to known variations in biomarkers across species and knowledge that proteins found in human samples would not necessarily translate to animal samples. Applicant further cites [0008] of the instant specification as disclosing “human blood tests for cancer marker proteins do not normally detect animal proteins so there are fewer available blood tests in veterinary oncology.” Applicant further cites Examples 6-7 of the instant specification as showing detecting the level of cell free nucleosomes containing histone isoform H3.1 successfully distinguished between healthy dogs and those with hemangiosarcoma or lymphoma. Applicant further argues there is no evidence to support the Office’s position that step ii of claim 1 is “conventional or routine” and the non-routine nature of step ii (“contacting the plasma sample obtained from the subject with a binding agent to detect a level of cell free nucleosomes containing histone isoform H3.1”) is evidenced by the lack of prior art relating to detecting nucleosome markers in non-human animals. Based on said arguments, Applicant states the present invention is a non-routine, practical application in the form of a diagnostic or monitoring method and that it cannot follow that the presently claimed method is a mere correlation without significantly more.
The arguments found in the Reply of 12/12/25 have been carefully considered, but are not deemed persuasive. In regard to the arguments that one of ordinary skill in the art would not have regarded using non-human mammal samples as routine or conventional due to known variations in biomarkers across species and knowledge that proteins found in human samples would not necessarily translate to animal samples, that there is no evidence to support the Office’s position that step ii of claim 1 is “conventional or routine” and the non-routine nature of step ii (“contacting the plasma sample obtained from the subject with a binding agent to detect a level of cell free nucleosomes containing histone isoform H3.1”) is evidenced by the lack of prior art relating to detecting nucleosome markers in non-human animals, the examiner disagrees. Detection of biomarkers, including nucleosome markers, in non-human mammalian samples is routine in the art (see detection of circulating histone H3 in mouse serum and plasma samples with histone H3-specific antibodies of an ELISA at the left column on page 2 of Ito et al (Journal of Intensive Care, 2018, 6(79): 1-6); see detection of histone H3 in canine PBMC samples with histone H3-specific antibodies of an Immunofluorescence assay at the right column on page 4835 of Wittenburg et al (Clin Cancer Res, 2010, 16(19): 4832-4842); see detection of histones in cow milk and serum samples using histone-specific antibodies at Figures 2 and 8 of Waga et al (Biochem J, 1987, 244: 675-682).
In regards to the citation of [0008] as disclosing “human blood tests for cancer marker proteins do not normally detect animal proteins so there are fewer available blood tests in veterinary oncology.”, the examiner notes the last paragraph on page 29 of the instant specification acknowledges: “Most assays for human proteins are not transferable to other animals. However, the structure of nucleosomes is highly conserved across species and even phyla.” In the prior art, the abstract of Waterborg (Biochem Cell Biol, 2012, 90: 79-95), the left column on page 904 of Bruchim et al (Cell Stress and Chaperones, 2017, 22: 903-910), and the left column on page 2 of Ito et al all also describe histone H3 proteins as “highly conserved.” Further, likely due to the highly conserved structures of histones across species, the left column on page 2 of Ito et al teaches detecting histone H3 in mouse serum and plasma samples using an H3-specific ELISA with an antibody that recognizes an epitope of H3 that “completely matched between humans, calves, mice, and rats.” Further, the prior art teaches detecting histones in non-human blood samples (see Abstract of Ito et al and Fig. 8 of Waga et al).
The examiner acknowledges Examples 6-7 of the instant specification as showing detecting the level of cell free nucleosomes containing histone isoform H3.1 successfully distinguished between healthy dogs and those with hemangiosarcoma or lymphoma.
In regards to the statement that the present invention is a non-routine, practical application in the form of a diagnostic or monitoring method and that it cannot follow that the presently claimed method is a mere correlation without significantly more, the examiner maintains that the rejected claims are not patent eligible because the claims are directed to abstract ideas and natural phenomenon because the claims recite natural phenomenon and abstract ideas (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). In the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (when considered both individually and as an ordered combination) are limited to well-understood, routine and conventional limitations of contacting plasma samples from a subject with binding agents known to detect, measure, and/or characterize cell free nucleosomes and optionally measure protein such as an interleukin (“Step 2B”).
Conclusion
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/SEAN E AEDER/ Primary Examiner, Art Unit 1642