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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/30/2025 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Status of Claims
Applicant’s amendment filed 10/30/2025 is acknowledged. Claims 26-29 and 31-32 have been amended. Claims 36-38 have been added. Claims 1-25 and 35 have been cancelled. Claims 26-34 and 36-38 are pending in the instant application and are the subject of this non-final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
Previous Rejection
Status of Prior Rejections/Objections:
The 112(b) rejections to claim(s) 28 is/are withdrawn in view of the amendments to the claims.
The 101 rejections are maintained and modified to improve clarity and in view of the amendments.
The prior art rejection(s) under 35 USC 103 directed to claim(s) 26-34 as being unpatentable over Husain in view of Lassig; to claim 30 over Hussain, Lassig, and Sako; to claim 35 over Hussain, Lassig, and Choi are withdrawn to accelerate compact prosecution.
The non-statutory double patenting rejections to copending applications 17/831,103, 17/834,663, 18/435,187 are maintained and modified in view of the amendments.
New Ground(s) of Rejections
Claim Rejections - 35 USC § 101
Claims 26-34 and 36-38 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) without significantly more. The claim(s) recite(s) abstract ideas/natural phenomena. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, the claims are directed to a process/method
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)? Yes
Claim 1 is directed to detecting a mutation or variant indicative of head and neck cancer comprising detecting a mutation or variant indicative of the cancer in genetic material isolated from drain fluid obtained from a head and neck surgery. Detecting encompasses at least the abstract idea of a mental process (e.g., observation, evaluation, and/or judgment of data indicative of said mutation/variant, such as looking through sequencing results and detecting/observing a difference between reads or evaluating a picture of an RFLP gel for hotspot mutations by observing it). See MPEP 2106.04(a)(2)(III).
Such a detection is further directed to the natural phenomena of the existence of a mutation or variant present in genetic material isolated from the drain fluid of a head and neck surgery and the correlation with said mutation or variant with a head and neck cancer (e.g., minimum residual disease). See 2106.04(b)(I), especially x: the existence of cell-free fetal DNA (cffDNA) in maternal blood, Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015) and v: a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). Such an interpretation is also supported by the instant specification (e.g., para [0053]). See MEP 2106.04(b)(I).
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application? No.
Regarding claim 26, the claim recites obtaining drain fluid from a … surgery, isolating genetic material from the drain fluid, and detecting a mutation or variant indicative of the [head and neck] cancer in the genetic material.
The steps of obtaining drain fluid and isolating genetic material are generically recited and obtaining a sample and isolating genetic material from said sample is well known, conventional, and routine within the art (e.g., Trigg RM, et al. Factors that influence quality and yield of circulating-free DNA: A systematic review of the methodology literature. Heliyon. 2018 Jul 25;4(7):e00699.: Abstract: “cfDNA … as a liquid biopsy of cancer for early detection …4172 articles identified through the database search” and “evaluated … choice of specimen … methods of cfDNA isolation and quantification”).
Thus, the claim fails to integrate the judicial exception(s) into a practical application.
Regarding claim 27, the claim further limits to particular genetic material. Such selects the particular data source to be manipulated in the judicial exception and/or represents a subset of isolating techniques that are well-known and conventional data gathering (see Trigg above). See MPEP 2105.06(g). Thus, the claim fails to integrate the judicial exception(s) into a practical application.
Regarding claim 29, the claim recites a particular type of head and neck cancer. Such represents a modification of the abstract idea and/or natural phenomena, and thus fails to integrate the claim.
Regarding claim 30, the claim recites a limitation of when the sample is collected (thus potentially limiting the genetic material collected in a specimen). Such represents a limitation on the data source to be manipulated as part of the judicial exception and is thus insignificant extra-solution activity. See MEPE 2106.05(g).
Regarding claim 31, the claim recites that the detecting comprises sequencing. Sequencing is well-known and conventional activity when recited at such a high level of generality. See MPEP 2106.05(d)(II), e.g., vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014).
Regarding claim 32, the claim recites that the method further comprises quantifying the mutation or variant indicative of the cancer. Such recites the same judicial exceptions discussed in claim 32 with the addition of mathematical calculation, including those that may be performed by the human mind (e.g., counting the number of sequences that include a mutation or variant). Thus directed to a judicial exception, it also fails to integrate the claim into a practical application.
Regarding claim 33, the claim recites further assessing a likelihood of minimum residual disease. Such encompasses the abstract ideas of mental processes and mathematical calculations, including those that may be performed by the human mind (e.g., forming a judgment about the likelihood and/or calculating a probability of MRD). Such is also directed to the natural phenomenon of the correlation between a mutation or variant and residual disease. Thus, the limitation fails to integrate the claim into a practical application as it requires no more than further judicial exceptions.
Regarding claim 34, the claim recites that the obtaining is performed using a surgical drainage tube. Such represents the selection of data, i.e., insignificant extra-solution activity, not least because the drain fluid collected from a surgical tube may have a different set of genetic material than that from a bandage exposed to the skin, for example.
Further, collecting the drainage by surgical drain is well-known, routine, and conventional (e.g., Doyle, G.R. and McCutcheon, J.A. (2015) 4.7 drain management and removal, Clinical Procedures for Safer Patient Care. Available at: https://opentextbc.ca/clinicalskills/chapter/4-8-drain-management-and-removal/ (Accessed: 16 December 2024): para 1-2: “Drains systems are a common feature of post-operative surgical management and are used to remove drainage from a wound bed to prevent infection and the delay of wound healing… Drainage tubes consist of silastic tubes with perforations to allow fluid to drain from the surgical wound site… The drainage is collected in a closed sterile collection system/reservoir (Hemovac or Jackson-Pratt)”; Emptying a Closed Wound Drainage System).
Thus, the limitation fails to integrate the claim into practical application.
Regarding claims 28, 36-38, the claim recites selecting further selecting a therapeutic treatment based on the detecting (claims 28 and 36) or an additional treatment based on the quantifying (claim 37 and 38).
First, selecting encompasses an abstract idea of a mental process (e.g., a clinician forming a judgement about which treatment would be best).
Second, as described in MPEP 2106.04(d)(2), if a claim fails to actually provide a treatment or prophylaxis, i.e., merely “selecting” a treatment, it is insufficient to integrate the claim into a practical application under the treatment or prophylaxis consideration.
Third, for the sake of compact prosecution, even should the claims be amended to recite administering the selected treatment, a generically recited therapeutic treatment would not meet the requirement that a treatment be “particular” because it may encompass all applications of the judicial exception(s). For example, selecting and administering acetaminophen, which may be administered to any patient recently having undergone head and neck surgery, would amount to no more than mere instruction to “apply” the exception in a generic way and have no more than a nominal or insignificant relationship to the judicial exception.
Fourth, for the sake of compact prosecution, it is noted that active surveillance would not represent a particular treatment. AH&NS (Surveillance education [Internet]. American Head & Neck Society; 2019 Dec 06 [cited 2025 Dec 29]. Available from: https://web.archive.org/web/20191206023516/https://www.ahns.info/survivorship_intro/surveillance-education/) teaches that the standard recommendation is that patients undergo baseline imaging at 3-6 months after treatment completion, and that further routine imaging after 6 months for asymptomatic patients was undergoing active debate in the field at the time of filing (What imaging will I require during my surveillance period and when should I get it?). Thus, a common standard of care for all patients undergoing a head and neck surgery for a head and neck cancer encompasses, broadly interpreted, active surveillance with at least one imaging. For this reason, the “treatment” would not be considered particular to the detection of a mutation as it fails to have more than a nominal or insignificant relationship to the exceptions, should it be administered as a result of the detection.
For these reasons, the claims fail to integrate the claims into practical applications.
Step 2B. Does the claim amount to significantly more?
No, nothing in the claims amounts to significantly more. Each of the claims is directed to some combination of judicial exception with well-known, routine, and conventional activity recited at a high level of generality, insignificant extra-solution acidity, and/or mere instructions to “apply” the judicial exception (e.g., selecting a therapy). As detailed in MPEP 2106.05, an inventive concept cannot be furnished by the judicial exception and such additional limitations have not been found to be not sufficient to amount to “significantly more” when recited in a claim with a judicial exception by the Courts.
It is noted that if applicant wants the claims to be directed to the “laboratory methods” for isolating genetic material from drain fluid and for detecting mutations, specifying such methods at such a high level of generality will be ineffective as they encompass well-understood, routine, and conventional methods of laboratory analysis. The courts have made clear in Ariosa that even if the sample were novel, applying well-understood, routine, and conventional activity to a natural phenomenon is insufficient to result in subject matter eligibility.
Claim Rejections - 35 USC § 103
Claim(s) 26-29, 31-34, and 36-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bellairs (Bellairs JA, et al. Tumor DNA: an emerging biomarker in head and neck cancer. Cancer Metastasis Rev. 2017 Sep;36(3):515-523) in view of Lassig (Lassig AAD, et al. Association of Oral Cavity and Oropharyngeal Cancer Biomarkers in Surgical Drain Fluid With Patient Outcomes. JAMA Otolaryngol Head Neck Surg. 2017 Jul 1;143(7):670-678; as cited in the IDS dated 06/17/2022).
Regarding claim 26-27, 29, 31-33, Bellairs teaches a method of detecting a mutation or variant indicative of head and neck cancer (throughout document, e.g., pg. 520, Utility of tumor DNA in head and neck cancer and Table 1), wherein DNA collected from bodily fluids provides a broader profile of the tumor compared to a single-site biopsy (pg. 516, col 2, para 1) and accounts for tumor heterogeneity because tumor DNA is shed throughout a primary tumor and from metastatic lesions (pg. 518, col 1, para 3).
Bellairs teaches isolating tumor-specific [i.e., containing gene mutations identified from biopsy samples] ctDNA (instant claim 27; see also pg. 517, col 1, para 1) from HNSCC patients (pg. 520, col 1, para 1). Bellairs teaches that tumor DNA, as determined by the presence of somatic mutations, is highly specific for HNSCC and can be used to identify HNSCC across multiple anatomic subsites (pg. 520, col 2, para 2, spanning pg. 521). Bellairs teaches utilizing such methods in oropharyngeal tumors (instant claim 29), including for post-surgery surveillance (pg. 520, col 2, para 1).
Bellairs teaches applying next-generation sequencing to tumor-specific genetic mutations (instant claim 31; pg. 521, col 1, para 2-3; Abstract), and that such sequencing advances have made it possible to interrogate tumor-specific genetic mutations in other bodily fluids (pg. 521, col 1, para 3, spanning col 2). Bellairs teaches quantifying tumor DNA in bodily fluids (instant claim 32; pg. 517, col 1, para 2, spanning col 2).
Bellairs teaches that there currently is no effective way to screen patient and identify those that have [minimum] residual disease following surgery, and therefore likely benefit from additional treatment, and suggests using ctDNA as a marker for disease recurrence [i.e., assessing a likelihood of minimum residual disease] (instant claim 33; pg. 518, col 2, para 2).
Bellairs teaches that tumor DNA is highly specific to malignant disease, is readily quantifiable, and half-life than proteins, allowing for superior tracking of tumor burden after successful therapeutic interventions (pg. 518, col 2, para 1). Bellairs teaches that tumor DNA is detectable from multiple fluid specimens dependent on the anatomic location of the tumor, and the amount of such tumor DNA shed depends on at least the size and location (pg. 517, col 1, para 1).
Bellairs fails to teach performing the obtaining, isolating of genetic material, and detecting mutations on drain fluid.
Lassig rectifies this by teaching measurement of biomarkers in postsurgical drain fluid for assessing cancer prognosis in oral and oropharyngeal squamous cell carcinoma (Abstract).
Lassig teaches that surgical drain fluid is routinely clinically collected and discarded, thereby adding no additional risk to the patient and little inconvenience to the investigator (Introduction, para 3). Lassig teaches that the tumor environment and surrounding postoperative wound serve as rich repositories for potential head and neck cancer biomarkers (Conclusion).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the postsurgical drain sample of Lassig in the method of detecting mutations indicative of cancer from isolated genetic material of Bellairs, motivated by the desire to utilize a sample the is a rich repository for head and neck cancer biomarkers and/or one that is routinely clinically collected such that it adds no risk to patients and little inconvenience to the investigator, as taught by Lassig.
Additionally and/or alternatively, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try such the sample of Lassig in the liquid biopsy technique of Bellairs and to utilize the tumor DNA as the prognostic marker, given the lack of effective ways to screen patients and identify those who have residual disease following surgery and would benefit from additional treatments such as adjuvant chemotherapy and the improved quantification and time relevance regarding treatments, as taught by Bellairs. It is identified that there is a finite number of potential ctDNA sources in proximity to a tumor, given the teachings of Bellairs regarding the anatomical location of a tumor, wherein such would have been predictable.
The artisan would have had a reasonable expectation of success under either motivation as Bellairs teaches that sequencing advances have made it possible to interrogate such tumor-specific genetic mutations in bodily fluids and both are directed to identifying markers of head and neck cancer outcomes. Such represents the application of known methods to a known specimen.
Regarding claim 30, in the method of Bellairs and Lassig, Lassig teaches evaluating biomarkers in fluid samples collected after the first post operative 8-hour shift in the morning of post-operative day 1, wherein a shift is an 8-hour sequence would fluid collection period [i.e., at about 24 hours, dependent on when the patient had their surgery].
Lassig teaches removal of drains based on clinical criteria (Abstract).
Further, such is a matter of routine optimization based on at least clinical availability (e.g., patient surgery end and sleep schedules, clinical staff availability, and patients meeting clinical criteria [for example, drainage amount]) and volume of drain fluid required for the particular assay chosen (e.g., a more sensitive assay may require less fluid, which may allow the artisan to end the collection earlier, but also may depend on patient-to-patient variability).
Regarding claim 28 and 36-38, in the method of Bellairs and Lassig, Bellairs teaches that the utility of tumor DNA is that it allows for both tumor characterization and quantification, wherein a minimally invasive liquid biopsy addresses tumor heterogeneity and can be used to design personalized therapies as well as to allow quantified monitoring of tumor burden during and post-treatment (pg. 521, col 1, para 3, spanning col 2; Abstract). Bellairs teaches designing therapeutic strategies targeting both primary mutations as well as minor sub population mutations that could confer treatment resistance (instant claim 28; pg. 519, col 1, para 3).
Bellairs teaches that current courses of treatments for HNSCC include one or more of surgery, radiation, and/or chemotherapy and that these are chosen based on radiographic disease staging primarily (pg. 516, col 1, para 1). Bellairs teaches that there is ongoing work to risk stratify and treat HNSCC patients on the basis of one molecular status of cancers (pg. 516, col 1, para 1; see also pg. 520, col 1, para 1, spanning col 2), and teaches as genetic characterization is emerging as a tool to risk stratify patients (pg. 518, col 2, para 2). Bellairs teaches that the therapies are associated with significant morbidities that may drastically affect post-treatment quality of life, and that treatment de-intensification in low-risk patients may allow for decreasing treatment-related morbidity and maintaining established survival outcomes (pg. 516, col 1).
Bellairs teaches utilizing ctDNA as a marker for disease recurrence in colorectal cancer after curative surgery, wherein patients with post-operative detection of ctDNA suffered a disease recurrence and those with no detectable post-operative ctDNA remained disease free, wherein Bellairs recommends those who have a risk of residual disease would benefit from adjuvant chemotherapy (pg. 518, col 2, para 2).
Thus, while Bellairs does not explicitly teach selecting a treatment based on the quantified amount a mutation/variant in head and neck cancer and a specific treatment based on a detected mutation/variant, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to both utilize the mutation/variant indicative of cancer detected in the selection of a personalized therapy (e.g., targeted at the mutations) and to utilize the quantified amount (inclusive of “below a detectable amount” or “any”) to stratify patients for personalized therapy, whereby substituting for or adding these stratification methods to the current method of radiographic disease staging would have been obvious. The artisan would have been so motivated in order to reduce the morbidities associated with treatments while maintaining survival outcomes, thereby potentially improving post-treatment quality of life beyond what is achievable with current stratification methods, as taught by Bellairs. Such would have been predictable as Bellairs teaches all the elements and such represents the application of known techniques to a known method.
Regarding claim 34, in the method of Bellairs and Lassig, Lassig teaches Lassig teaches obtaining drain fluid from a surgery with a surgical drainage tube (pg. 671, col 1, para 3, spanning col 2 through col 2, para 2: “standard 10-mm flat silicone surgical drains … Surgical drain fluid samples were collected”).
Claim(s) 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bellairs (Bellairs JA, et al. Tumor DNA: an emerging biomarker in head and neck cancer. Cancer Metastasis Rev. 2017 Sep;36(3):515-523) in view of Lassig (Lassig AAD, et al. Association of Oral Cavity and Oropharyngeal Cancer Biomarkers in Surgical Drain Fluid With Patient Outcomes. JAMA Otolaryngol Head Neck Surg. 2017 Jul 1;143(7):670-678; as cited in the IDS dated 06/17/2022) as applied to claim 26 above, and further in view of Sako (Sako K, et al. A Study of Wound Drainage Fluid for Tumor Cells as a Source of Recurrence. Am J Surg. 1963 Nov;106:797-801).
Regarding claim 30, in the method disclosed and suggested by Bellairs and Lassig, Lassig teaches evaluating biomarkers in fluid samples collected after the first post operative 8-hour shift in the morning of post-operative day 1, wherein a shift is an 8-hour sequence would fluid collection period [i.e., at about 24 hours, dependent on when the patient had their surgery].
Under a narrow interpretation of within about 24 hours, Lassig fails to explicitly teach collecting the surgical drainage fluid within about 24 hours as the timing of patient surgeries on post-operative day zero is unknown.
Sako rectifies this by teaching wound drainage fluid from patients who had undergone clinically curative resections for cancer in twenty four hour samples. Sako further teaches that samples from the first 24 hour period ran as high as 150 cc. of drainage [i.e., the highest volume of drainage production period within 72 hours] and that 2/3 patients with positive drainage in the 0-24 hour period had recurrence within the follow-up period whereas no patients with positive drainage at 24-48 or 48-72 hours had recurrence within the follow-up period (Table II).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize a collection of drain fluid within about 24 hours taught by Sako in the method of Bellairs in view of Lassig, motivated by the desire to gain the highest amount sample and/or to have the highest chance of predicting recurrence, as taught by Sako. There would be a strong expectation for success as all are directed to identifying recurrence in head and neck cancers and such represents the application of a known technique to a known method.
Double Patenting
Claims 26-34 and 36-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/831,103 in view of Avila (Avila M, Meric-Bernstam F. Next-generation sequencing for the general cancer patient. Clin Adv Hematol Oncol. 2019 Aug;17(8):447-454).
Both sets of claims are directed to isolating a nucleic acid from a surgical drainage sample and detecting and quantifying a plurality the nucleic acids such that the results indicate minimum residual disease (claim 1) and that the surgery may be a neck surgery (claim 6). ‘103 recites that the assay is a surgical margin assay (claim 1) and that the surgery may be a dissection surgery (claim 2) and the sample may comprise at least cfDNA and tumor samples (claim 3).
It is noted that obtaining a sample would have been required in order to possess one for the step of isolation and thus would be inherently taught.
It is noted that the instant claims teach that the head and neck surgery may be directed to an oropharyngeal [i.e., throat] cancer and that the neck surgery, which may be a dissection, of ‘103 may be broadly interpreted as a head and neck surgery in the context of a surgical margin assay for tumor cells at least because of routine optimization of surgeons in the operating room may expand the scope of the intended operation for cancers to get an appropriate margin based on observed growth once the patient is opened up. A neck dissection would be understood by the artisan as a removal of cancerous lymph nodes and surrounding tissues.
Both sets of claims are directed to methods involving sequencing (claim 4); selecting an additional treatment based on the assay (claim 8), wherein the additional treatment incudes at least chemotherapy (claim 9); capturing the fluid using a drainage tube (claim 10) within about 24 hours (claim 11).
The claims of ‘103 fail to explicitly state that the assay results detect and quantify a mutation or variant indicative of cancer.
Avila rectifies this by teaching that sequencing detects differences in specific DNA sequences between a sample and a reference genome or matched normal DNA (Abstract), wherein such mutations may be drivers of cancer growth and thus represent therapeutic opportunities and is therefore used to guide treatment decisions (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the method of identifying mutations/variants indicative of cancer in the method of detecting and quantifying of ‘103 comprising sequencing nucleic acids from surgical drain fluid, motivated by the desire to better guide treatment decisions by targeting drivers of cancer growth that represent therapeutic opportunities, as taught by Avila. Such would have been predictable as both are directed to the analysis of nucleic acids originating from sources including tumor cells and represents the application of a known technique to a known method.
Claims 26-34 and 36-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/834,663 in view of Avila (Avila M, Meric-Bernstam F. Next-generation sequencing for the general cancer patient. Clin Adv Hematol Oncol. 2019 Aug;17(8):447-454).
Both sets of claims are directed to isolating a nucleic acid from a surgical drainage sample and detecting and quantifying the nucleic acids such that the results indicate minimum residual cancer (claim 1), wherein the nucleic acid is HPV viral DNA that indicates oropharyngeal squamous cell carcinoma within the subject following a resection surgery (claim 18; see also claims 2 and 3). It follows that such a resection would be in the oropharyngeal location [i.e., in the throat between the head and neck].
Both sets of claims are directed to selecting a treatment based on the detection and quantification (claims 6-7), obtaining the drain fluid from a tube (claim 8) within 24 hours (claim 9), and performing sequencing (claim 4). Both sets of claims are directed to nucleic acids from samples comprising cfDNA and tumor cells (claim 3).
The claims of ‘663 fail to explicitly state that the assay results detect and quantify a mutation or variant indicative of cancer.
Avila rectifies this by teaching that sequencing detects differences in specific DNA sequences between a sample and a reference genome or matched normal DNA (Abstract), wherein such mutations may be drivers of cancer growth and thus represent therapeutic opportunities and is therefore used to guide treatment decisions (Abstract).
and that the surgery may be a neck surgery (claim 6). ‘103 recites that the assay is a surgical margin assay (claim 1) and that the surgery may be a dissection surgery (claim 2) and the sample may comprise at least cfDNA and tumor samples (claim 3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to utilize the method of identifying mutations/variants indicative of cancer in the method of detecting and quantifying of ‘103 comprising sequencing nucleic acids from surgical drain fluid, motivated by the desire to better guide treatment decisions by targeting drivers of cancer growth that represent therapeutic opportunities, as taught by Avila. It further would have been obvious to apply the method of ‘103 in view of Avila to the OPSCC resection of claim 18 in addition and/or in substitute of the HPV viral DNA, motivated by the desire to determine a minimal residual cancer. Such would have been predictable as all are directed to the analysis of nucleic acids originating from sources including tumor cells and represents the application of a known technique to a known method.
Claims 26-34 and 36-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/435,187 in view of Bellairs (Bellairs JA, et al. Tumor DNA: an emerging biomarker in head and neck cancer. Cancer Metastasis Rev. 2017 Sep;36(3):515-523) and Lassig (Lassig AAD, et al. Association of Oral Cavity and Oropharyngeal Cancer Biomarkers in Surgical Drain Fluid With Patient Outcomes. JAMA Otolaryngol Head Neck Surg. 2017 Jul 1;143(7):670-678; as cited in the IDS dated 06/17/2022).
Both claims are directed to a method of obtaining effluent from a patient having undergone a surgery, identify a presence or absence of a biomarker indicative of disease in the sample (claim 1) wherein the biomarker comprises circulating tumor cells and cell-free DNA (claim 10) and indicates minimum residual disease (claim 8) and wherein the sample may be obtained at or near the time of the surgery (claim 2) [i.e., within about 24 hours].
‘187 fails to explicitly teach detecting a mutation or variant indicative of the cancer, selecting therapy based on the detecting/quantifying, sequencing, that the sample may be obtained with a surgical drainage tube, or particular treatments that may be selected.
Bellairs teaches that despite global advances in cancer care, HNSCC often presents with advanced disease and associated with poor 5-year survival, and that while genotyping to guide clinical decision-making is becoming commonplace in modern oncology, the management of HNSCC, tissue biopsies remain the mainstay despite being temporally and spatially limited (Abstract).
Bellairs teaches that applying next-generation sequencing to tumor-specific genetic mutations (pg. 521, col 1, para 2-3; Abstract), and that such sequencing advances have made it possible to interrogate tumor-specific genetic mutations in other bodily fluids (pg. 521, col 1, para 3, spanning col 2). Bellairs teaches quantifying tumor DNA in bodily fluids (pg. 517, col 1, para 2, spanning col 2).
Bellairs teaches that tumor DNA is detectable from multiple fluid specimens dependent on the anatomic location of the tumor, and the amount of such tumor DNA shed depends on at least the size and location (pg. 517, col 1, para 1).
Bellairs teaches that the utility of tumor DNA is that it allows for both tumor characterization and quantification, wherein a minimally invasive liquid biopsy addresses tumor heterogeneity and can be used to design personalized therapies as well as to allow quantified monitoring of tumor burden during and post-treatment (pg. 521, col 1, para 3, spanning col 2; Abstract). Bellairs teaches designing therapeutic strategies targeting both primary mutations as well as minor sub population mutations that could confer treatment resistance (pg. 519, col 1, para 3).
Bellairs teaches that current courses of treatments for HNSCC include one or more of surgery, radiation, and/or chemotherapy and that these are chosen based on radiographic disease staging primarily (pg. 516, col 1, para 1). Bellairs teaches that there is ongoing work to risk stratify and treat HNSCC patients on the basis of one molecular status of cancers (pg. 516, col 1, para 1; see also pg. 520, col 1, para 1, spanning col 2), and teaches as genetic characterization is emerging as a tool to risk stratify patients (pg. 518, col 2, para 2). Bellairs teaches that the therapies are associated with significant morbidities that may drastically affect post-treatment quality of life, and that treatment de-intensification in low-risk patients may allow for decreasing treatment-related morbidity and maintaining established survival outcomes (pg. 516, col 1).
Bellairs teaches utilizing ctDNA as a marker for disease recurrence in colorectal cancer after curative surgery, wherein patients with post-operative detection of ctDNA suffered a disease recurrence and those with no detectable post-operative ctDNA remained disease free, wherein Bellairs recommends those who have a risk of residual disease would benefit from adjuvant chemotherapy (pg. 518, col 2, para 2).
Lassig teaches obtaining drain fluid from a surgery with a surgical drainage tube (pg. 671, col 1, para 3, spanning col 2 through col 2, para 2: “standard 10-mm flat silicone surgical drains … Surgical drain fluid samples were collected”).
Lassig teaches that surgical drain fluid [from oropharyngeal cancers] is routinely clinically collected and discarded, thereby adding no additional risk to the patient and little inconvenience to the investigator (Introduction, para 3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine the method of ‘187 with the methods of applying sequencing stratifying patients using quantified tumor DNA comprising mutations/variants of Bellairs, wherein it would be obvious to collect the effluent from HNSCC patients with the drain tube of Lassig. The artisan would be so motivated by the desire to address the poor survival, lack of good genotyping methods and issues with treatment-related morbidities, described by Bellairs, using the advances in quantifying that enable such stratification for determining minimum residual disease, taught by Bellairs, and/or to address tumor heterogeneity, as taught by Bellairs. The artisan would further be motivated to utilize the surgical drain fluid of Lassig at because it is already routinely collected and does not pose any additional risk to patients and little inconvenience to clinicians, as taught by Lassig. Such would have a high expectation of success as all are directed to the detection of tumor-related biomarkers and improving treatments for patients.
Response to Arguments
Applicant's arguments filed 10/30/2025 have been fully considered but they are not persuasive.
Applicant argues, regarding the 101 rejection, that the instant claims are eligible under step 2A of the Alice/Mayo framework. Applicant alleges that the pending claims do not “recite” a judicial exception as the presence of tumor-associated material in a drain fluid is not what is claimed; rather, the claims allegedly recite laboratory methods for isolating genetic material from drain fluid and detecting mutations and/or variants indicative of cancer in the isolated genetic material. Applicant argues that it is impossible that the claim elements constitute a natural phenomenon because none of the steps occur or could occur in nature, thus the claims allegedly relate patent eligible material.
The arguments presented are substantially similar to those previous addressed and do not overcome the rejection. However, in an effort to advance prosecution, the rationales have been expanded and clarified here.
Regarding the argument that the presence of tumor-associated material in drain fluid is not what is claimed and that applicant is allegedly claiming laboratory methods, the claims unambiguously recite “detecting a mutation … indicative of the cancer in the genetic material [isolated from the drain fluid]”. MPEP 2106.04(b) makes clear that the Courts have found that concepts such as the correlation between a mutation and a particular cancer or the existence of such a mutation in a particular specimen type may be considered natural phenomenon exclusions as they reflect the Supreme Court’s view that the basic tools of science and technological work are not patentable.
In particular, the facts of these claims closely mirror those of the previously cited Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015), which the Courts have found to be ineligible under 101. Claims 24 and 25 are copied here for convenience:
24. A method for detecting a paternally inherited nucleic acid on a maternal blood sample, which method comprises:
removing all or substantially all nucleated and anucleated cell populations from the blood sample,
amplifying a paternally inherited nucleic acid from the remaining fluid and subjecting the amplified nucleic acid to a test for the Paternally [sic] inherited fetal nucleic acid.
25. A method for performing a prenatal diagnosis on a maternal blood sample, which method comprises
obtaining a non-cellular fraction of the blood sample
amplifying a paternally inherited nucleic acid from the non-cellular fraction
and performing nucleic acid analysis on the amplified nucleic acid to detect paternally inherited fetal nucleic acid.
As with the instant claims, the detection of the paternal cffDNA was identified as directing the claim to a natural phenomenon. While the Applicant argues that it is “impossible” that the claim elements constitute such natural phenomenon because none of the steps occur in nature, as may be seen above claim 24 comprises a narrower step of “isolating” and claim 25 comprises a step of “obtaining”. These claims were found by the Courts to be subject matter ineligible because the claims recite only what was well-understood and routine at the time of their filing—far earlier, it is noted, than the instant date of filing.
Further, regarding the argument that these claims merely “involve” the presence of the mutations/variants rather than recite them, as with the claims of Ariosa, given that the instant claims begin and end with the judicial exception this is not found to be persuasive. The claims recite no more than what is well-known, routine, and conventional at a high level of generality and/or further encompass further judicial exceptions where the purpose is to enable the artisan to detect the natural phenomenon. The purpose of the “non-natural” steps is not to transform the genetic material from the drain fluid; it is to apply the judicial exception. Isolation of nucleic acids is not a material transformation for the purposes of excluding such from natural phenomenon. See MPEP 2106.04(c)(II)(C)(2). Therefore, the examples of the material transformations recited in MPEP 2106.04(b)(I) serve to illustrate the differences between what would not be considered a natural phenomenon and the concepts at issue here, which would.
While further limitations may transform the claims such that they merely “involve” the natural phenomena, the inventive concept currently remains with the detection of a mutation/variant indicative of cancer originating from drain fluid rather than with the methods through such the detection is accomplished. MPEP 2106.05(I) makes clear that the inventive concept cannot be furnished by the natural phenomenon and/or abstract idea itself/themselves.
While the Applicant may disagree with the conclusions of Ariosa, they are precedential and binding on the Office. The mere assertion that the claims do not recite natural phenomena remains insufficient to overcome the rejection.
Regarding the art rejections, new art has been applied in an effort to advance prosecution. Bellairs does teach a variety of biological samples and shedding of tumor DNA in proximity; therefore, it would be predictable to use the sample of Lassig. Therefore, the artisan would have had a reasonable expectation of success. And Lassig teaches at least that such a sample is routinely clinically collected and poses no risk to patients and little inconvenience clinicians, thereby motivating its use. Thus, such a combination would have been obvious before the effective filing date.
Regarding the double patenting rejections, while the dates are noted, these rejections are not the only outstanding rejections. Therefore, the provision to withdraw them is not yet applicable.
Conclusion
No claims are allowed.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636