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 .
Detailed Action
The Amendments and Remarks filed 7/1/26 in response to the Office Action of 2/3/26 are acknowledged and have been entered.
Claims 31-32 have been added by Applicant.
Claims 1, 2, 8-11, 14, 15, 17-26, and 28-32 are pending.
Claims 1, 14, 15, and 29 have been amended by Applicant.
Claims 1, 2, 8-11, 14, 15, 17-26, and 28-32 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections Maintained
Claim Rejections - 35 USC § 101
Claims 1, 2, 8-11, 14, 15, 17-26, and 28-30 remain rejected and claims 31-32 are 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 28-32 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” steps of claim 1, 14, and 29 and (ii) the “comparing” step of claim 14. 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 obtaining a sample from a subject and contacting the samples from a subject with a binding agent (“Step 2B”). Methods of obtaining and contacting a sample, such as a plasma sample, from a subject with binding agents (such as a binding agent used 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 previously 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). In particular regards to Micallef et al, the instant specification acknowledges detecting levels cell free nucleosomes of tumor origin are known in the prior art: “As previously reported in WO 2016/067029 (incorporated herein by reference), particular histone variants, such as histone H3.1, H3.2 or H3t, may be used to isolate cell free nucleosomes originating from tumour cells. Therefore, the total level of cell free nucleosomes of tumour origin may be detected.” (see first full paragraph on page 6 of the instant specification). 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 instant 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). Further, the instant specification acknowledges a “two-site” immunoassay ELISA are known to be used to characterize exosomes by capturing the exosomes with an anti-nucleosome binding agent and then using a second antibody to characterize the exosomes (second full paragraph on page 7, 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 7/1/26, applicant submitted a declaration by Jacob Vincent Micallef. Applicant argues it would not have been considered routine or conventional to determine the level of H3.1-nucleosome in plasma. Applicant further argues no liquid biopsy tests were available on the veterinary market at the time of filing the instant application. Applicant further argues detection of biomarkers, including nucleosome markers, in non-human mammals is not routine. Applicant further argues previously cited Ito et al., Wittenburg et al., and Waga et al are related to measurement of free histone proteins and not circulating cell free nucleosomes. Applicant further argues there is no evidence that determining the level of circulating cell free nucleosomes, let alone specifically those containing H3.1, in plasma is routine or conventional. Applicant further argues that a “conserved structure” of histones does not establish that circulating cell-free nucleosomes containing H3.1 in plasma would reasonably be expected to function as a cancer biomarker in the plasma of non-human mammals or that such detection would be diagnostically meaningful. Applicant further argues that cited references do not teach or suggest the claimed diagnostic application. Applicant further cites MPEP 2106.05(I)(A)(v) and argues the claimed step of determining the level of cell free nucleosomes containing histone isoform H3.1 in a plasma sample from non-human mammals should be considered “a specific limitation other than what is well-understood, routine, conventional activity in the field, or [adding] unconventional steps that confine the claim to a particular useful application.”
The amendments to the claims, the declaration by Jacob Vincent Micallef, and the arguments found in the Reply of 7/1/26 have been carefully considered, but are not deemed persuasive. In regard to the citation of MPEP 2106.05(I)(A)(v) and arguments the claimed step of determining the level of cell free nucleosomes containing histone isoform H3.1 in a plasma sample from non-human mammals should be considered “a specific limitation other than what is well-understood, routine, conventional activity in the field, or [adding] unconventional steps that confine the claim to a particular useful application.”, that it would not have been considered routine or conventional to determine the level of H3.1-nucleosome in plasma, that detection of biomarkers (including nucleosome markers) in non-human mammals is not routine, and there is no evidence that determining the level of circulating cell free nucleosomes (let alone specifically those containing H3.1) in plasma is routine or conventional, the examiner disagrees. Citing the prior art of Micallef et al (WO 2016/067029), the instant specification acknowledges detecting levels cell free nucleosomes of tumor origin are known in the prior art: “As previously reported in WO 2016/067029 (incorporated herein by reference), particular histone variants, such as histone H3.1, H3.2 or H3t, may be used to isolate cell free nucleosomes originating from tumour cells. Therefore, the total level of cell free nucleosomes of tumour origin may be detected.” (see first full paragraph on page 6 of the instant specification). Further, the instant 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). Further, the instant specification acknowledges a “two-site” immunoassay ELISA are known to be used to characterize exosomes by capturing the exosomes with an anti-nucleosome binding agent and then using a second antibody to characterize the exosomes (second full paragraph on page 7, in particular). Further, the prior art of Cantor et al (US 2013/0230858 A1; 9/5/2013; 9/16/22 IDS) identifies both the QIA25 nucleosome ELISA kit and the Cell Death Detection ELISAPLUS ELISA as “commercially available” kits for detecting nucleosomes ([0294], in particular). Cantor et al describes detecting cell-free nucleosomes in blood ([0042], in particular). Cantor et al further describes such ELISA’s can capture nucleosomes with a first binding agent (such an antibody that binds histone H2A, H2B, H3, and H4) followed by binding with a second binding agent to further characterize the captured nucleosome ([0289], in particular). Cantor et al further describes using antibodies such as an antibody specific for histone H3.1 to characterize captured nucleosomes ([0296], in particular). Note that, while Cantor et al teaches using an antibody specific for histone H3.1 to characterize a nucleosome as “fetal” in methods of differentiating fetal from maternal nucleosomes, this is not a prior art rejection. Page 505 of Letendre et al (J Vet Emerg Crit Care, 2018, 28 (6): 503-511), page 261 of Bauquier et al, and page 264 of Jeffery et al (Veterinary Immunology and Immunopathology, 2015, 168: 262-268) all teach detecting cell free nucleosomes in plasma and/or blood samples from non-human subjects with the Cell Death Detection ELISAPLUS ELISA of Cantor et al. It would be considered conventional and routine to detect and characterize cell-free nucleosomes in plasma from non-human animals by using an ELISA to contact the cell-free nucleosomes with a binding agent that captures the nucleosomes and a second binding agent (such as an anti-histone H3.1 antibody) to characterize the captured nucleosomes because Cantor et al, Letendre et al, Bauquier et al, and Jeffery et al all teach using a commercially-available ELISA that detects and characterizes cell-free nucleosomes in such a manner (in addition to the instant specification acknowledging such assays are well-known in the art – at paragraph spanning pages 16-17, in particular).
In regards to the argument that no liquid biopsy tests were available on the veterinary market at the time of filing the instant application, the examiner disagrees. At the left column on page 505 of Letendre et al (J Vet Emerg Crit Care, 2018, 28 (6): 503-511), Letendre et al describes using a “commercial” ELISA of Bauquier et al (J Vet Intern Med, 2016, 30(1): 260-268) to detect concentrations of nucleosomes in plasma of canines. Footnotes and the right column on page 261 of Bauquier et al identify that commercial ELISA as Cell Death Detection ELISAPLUS and describe use of the ELISA to detect levels of nucleosomes in plasma samples of horses by contacting the plasma samples with an anti-histone antibody binding agent as well as an anti-DNA binding agent. At the left column on page 264 of Jeffery et al (Veterinary Immunology and Immunopathology, 2015, 168: 262-268), Jeffery et al also teaches using the same commercial ELISA to detect nucleosome levels in blood samples from canines. Further, Cantor et al (US 2013/0230858 A1; 9/5/2013; 9/16/22 IDS) identifies both the QIA25 nucleosome ELISA kit and the Cell Death Detection ELISAPLUS ELISA as “commercially available” kits for detecting nucleosomes ([0294], in particular). Cantor et al described detecting cell-free nucleosomes in blood ([0042], in particular). Cantor et al further describes such ELISA’s can capture nucleosomes with a first binding agent (such an antibody that binds histone H2A, H2B, H3, and H4) followed by binding with a second binding agent to further characterize the captured nucleosome ([0289], in particular). Cantor et al further describes using antibodies such as an antibody specific for histone H3.1 to characterize captured nucleosomes ([0296], in particular). Note that, while Cantor et al teaches using an antibody specific for histone H3.1 to characterize a nucleosome as “fetal” in methods of differentiating fetal from maternal nucleosomes, is it again noted that this is not a prior art rejection.
In regards to the argument that previously cited Ito et al., Wittenburg et al., and Waga et al are related to measurement of free histone proteins and not circulating cell free nucleosomes, such references were cited to address a previous argument that there is a “lack of prior art relating to detecting nucleosome markers in non-human animals.” Again, this is not a prior art rejection.
In regards to the argument that that a “conserved structure” of histones does not establish that circulating cell-free nucleosomes containing H3.1 in plasma would reasonably be expected to function as a cancer biomarker in the plasma of non-human mammals or that such detection would be diagnostically meaningful, the examiner agrees. However, this is not a prior art rejection.
In regards to the argument that cited references do not teach or suggest the claimed diagnostic application, this is not a prior art rejection. Further, a correlation between a biomarker and diagnosis is a “natural phenomenon” – which is a judicial exception (“Step 2A prong one”) and not a practical application of a judicial exception. 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”).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SEAN E AEDER/ Primary Examiner, Art Unit 1642
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