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
Claims 13 and 20-21 are cancelled. Claims 1, 11, and 17 have been amended as requested in the amendment filed on 21 November 2025. Following the amendment, claims 1-12 and 14-19 are pending in the instant application, and are under examination in the instant office action.
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 1-12 and 14-19 stand as rejected under 35 U.S.C. 101 because the claimed invention is directed to the abstract idea mental process judicial exception(s) of “analyzing” and “determining an amount” (independent claim 1) and/or “determining whether the thyroid nodule is, or is likely to become, cancerous” (independent claims 11 and 17), without significantly more.
On pages 5-6 of Remarks filed 21 November 2025, Applicant traverses the rejection on the following grounds. Applicant argues the Office disregards the practical application of the claim limitation because there is nothing abstract about the extracting limitation. Applicant asserts the claims have been further amended to recite additional features that are not well- understood, routine, or conventional activities previously known to the industry Applicant asserts the claims recite practical methods of sample collection and analysis integrate specific medical procedures and laboratory techniques to achieve a concrete, clinical result; and human-performed medical procedure-fine needle aspiration (FNA)-to extract tissue from a defined anatomical region. Thus, Applicant asserts, this is a concrete, physical and transformative step not a mental process. Applicant further asserts the analysis performed on the sample is not just data gathering because it yields a tangible result – an amount of DNT cells, and provides a real-world application to diagnostics, improving the field by prescribing where to collect the sample. Lastly, Applicant asserts that the claims now require sampling within and adjacent to a thyroid nodule, which is nonconventional sampling and, as an ordered combination, is novel in the art.
All of these arguments have been reviewed in full, but are not persuasive to overcome the rejection of record for the following reasons.
The claims are directed to methods, which are a statutory category of invention. (STEP 1: YES).
As currently amended the claims, however, still recite at least one judicial exception. As stated briefly above, the claims recite analyzing and determining, both of which are mental processes that is one of the enumerated abstract idea grouping that can be performed in the human mind. MPEP 2106.04(a) defines this grouping as concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III). The instant claims are analogous to claims directed to collecting information, analyzing it, and displaying results of the analysis, where the analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, that were deemed patent ineligible subject matter in Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016). Further, the claims recite determining steps, which were deemed patent ineligible subject matter in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014). Thus, the claims still recite at least one judicial exception (STEP 2A, Prong One: YES).
Prong Two of the analysis asks whether the elements/steps, in addition to the judicial exception, integrate the recited judicial exception into a practical application of the exception. See MPEP 2106.04(d). In the instant claims the additional steps provide none of the relevant considerations set forth in MPEP 2106.05(a-c), (e) and (h) that demonstrate integration. For example, the additional steps/elements provide no improvement in the relevant technology as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a). While depending claim 12 recites administering a treatment, this treatment is not particular to the application of the judicial exception itself, and therefore this administering step does not effect a particular treatment or prophylaxis for a disease or medical condition, as required by MPEP § 2106.04(d)(2). Furthermore, the administering step is contingent upon a “determination of whether the thyroid nodule is, or is likely to become, cancerous” and MPEP 2106.04(d)(2) states in order to qualify as a "treatment" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects treatment. Since administering is conditional, then this is not an affirmatively recited action. Additionally, there is no transformation to a different state or thing as discussed in MPEP § 2106.05(c). Lastly, the claims do not apply the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment (collecting and analyzing thyroid samples), such that the claim, as a whole, is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e). Thus, the claims as a whole are directed to the judicial exception itself since they provide no integration (Step 2A: NO), and the additional steps/elements of the claims require further analysis under Step 2B.
Step 2B requires that the steps/elements, recited in addition to the judicially excepted subject matter, amount to significantly more than the judicial exception(s) itself. In the instant case, the claims simply append well-understood, routine, conventional activities previously known to the industry, and specified at a high level of generality, to the judicial exception, see Alice Corp., 573 U.S. at 225, 110 USPQ2d at 1984 (see MPEP § 2106.05(d)). Within the claims and disclosure as filed, measuring the amount of double negative T cells is recited at a high level of generality such that the details for measuring are not disclosed other than reference to known methods (e.g. flow cytometry on page 20 of spec.). Similarly, analyzing is recited at such a high level of generality such that it does not impose meaningful limits upon the recited judicial exceptions. In the previous Office action, the Examiner has cited evidence that these steps/elements were known in the art before the effective filing date of the application (see Imam et al. 2014 cited on the ISR filed 30 June 2022). For all of these reasons, the claims as a whole fail to provide an inventive concept beyond what was well-understood, routine and conventional practice before the time of filing and amount to mere instructions to apply an exception to a field of use (MPEP 2106.05(f) (STEP 2B: NO).
For all of these reasons, the claims as a whole are directed to an abstract idea mental process judicial exception without significantly more, and claims 1-12 and 14-19 stand as are rejected under 35 U.S.C. 101.
Claim Rejections - 35 USC § 103 (New, Necessitated by Amendment)
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
(1) Claim 13 has been cancelled. As currently amended, Claims 1-9, 11-12, and 14-19 are rejected under 35 U.S.C. 103 as being unpatentable over Imam et al., 2014 (cited in the previous Office action) as evidenced by Yang et al., Diagnostic Cytopathology, Vol. 00 and No. 00, 2017 (DOI 10.1002/dc).
On pages 7-8 of Remarks filed 21 November 2025, Applicant asserts that Imam does not teach the newly added limitations: “wherein the area comprises a microenvironment surrounding the thyroid nodule with immune infiltration” (claim 1); the fine needle aspiration wherein the area comprises a microenvironment surrounding the thyroid nodule with immune infiltration (claim 11); and “wherein the area comprises a microenvironment surrounding the thyroid nodule with immune infiltration” (claim 17). Applicant argues the Imam et al. prior art teaches samples that were aspirated ex vivo from resected thyroid glands (citing Imam pg. 508, right column). Applicant states: “Imam only describes extracting a tissue sample from a thyroid nodule itself.”
While these arguments have been reviewed in full, they are not persuasive to overcome the rejection of record for the following reasons. The claims now recite a microenvironment “surrounding” the thyroid nodule with immune infiltration. The term “surrounding” is not explicitly defined within the specification. The instant disclosure uses the word “surrounding” in only two places and neither constitute a definition of what the term means. The specification states: At paragraph [00032] “Image showing a common immune infiltration surrounding thyroid cancer (FIG. 7A)”; and, the specification further states at [00051], “For the evaluation of the nodule microenvironment, needles are directed to the surroundings of the structural abnormality (i.e., to an area within and adjacent/intersection to the nodule)” (emphasis added). Thus, the “surrounding” of the instant claims appears to include areas within and intersecting with the nodule itself.
Regarding the teachings of Imam, a reference serves as prior art for all that it teaches and the Imam prior art discloses fine needle aspiration cytology was known in the art prior to filing and used to identify the patients referred for thyroid surgery in the clinical study. Imam states the patients include “those with positive or suspicious cytology for malignancy on fine-needle aspiration (FNA)” (pg. 506, last paragraph) and “Patients with FNA cytology consistent with Hashimoto thyroiditis (hypothyroid by history)” (pg. 509, second paragraph).
The sampling in Imam et al., however, uses ex vivo aspirated samples from resected thyroid nodules. Imam et al. teach “distinguishing the differences in lymphocytic infiltration (Fig. 1 top)” (pg. 509, second column). The fact that Imam and colleagues chose not to utilize the technique of FNA, which it clearly teaches was known in the art prior to filing, is immaterial to their ability to demonstrate a microenvironment of the thyroid nodule has immune infiltration, as claimed. Specifically, Imam et al. teach the samples comprise immune cells, the authors analyze the extracted tissue sample for macrophages and NK cells, and teach the method further comprising removing the patient's thyroid if the thyroid nodule is determined to be, or likely to become, cancerous based on the amount of double negative T cells present in the lymphocytes in the sample (as required by instant claims 7 and 19). Specifically, Imam and colleagues teach measuring an amount of double negative T cells (DNTs) in the tissue sample relative to other lymphocytes in the tissue sample. The authors teach double negative T cells are significantly elevated in papillary thyroid cancer (PTC) and Figure 3 demonstrates greater than 15% DNTs in the obtained sample indicates PTC, while a double negative T cell content less than 5% indicates Hashimoto thyroiditis (Figure 3), as recited by instant claim 17.
The Imam et al. prior art samples within the resected nodule itself and does not teach ultrasound-guided fine needle aspiration (FNA) of tissue adjacent/intersecting or surrounding the nodule. The Yang et al. prior art, however, remedies this deficiency. This new art was necessitated by Applicant’s amendment to the claim.
Yang et al. teach the ultrasound findings for overtly invasive encapsulated follicular variant PTC (EFVPTC) typically showed a round/oval nodule with irregular
margins (Abstract and Figure 4A). The ultrasound findings for infiltrative follicular variant of papillary thyroid carcinoma without a capsule (IFVPTC) also showed blurred margins (Abstract and Figure 2A). The authors define a suspicious ultrasound as having blurred or poorly defined margins (pg. 2, last paragraph). Therefore, Yang et al. conclude that the hallmark of infiltrated nodules is poorly defined, blurry or lobular margins (see Figure 2E). In contrast, encapsulated follicular variants have clear margins, little to no infiltration, and lower papillary thyroid carcinoma (PTC) suspicion (see the diagnosis flowchart in Diagram 2). The authors conclude: “ultrasound approximates gross pathology in our experience, and can detect overt invasion”.
It would have been obvious to a person having ordinary skill in the art that ultrasound-guided FNA tissue samples from an area within and adjacent to/intersecting with/surrounding a suspicious thyroid nodule could be used, as disclosed in Yang et al. These samples could have substituted for the samples in the methods of Imam et al. and subjected to the analysis for double negative T cells with predictable success. A skilled artisan would be motivated to use FNA instead of resected tissue because it is much less invasive a procedure than surgical resection and Yang et al. explicitly state blurred margins on ultrasound imply overt invasion. Since Yang et al. teach the margins of infiltrated nodules are blurry and ill-defined, sampling within and adjacent to the nodule would occur during FNA simply because the margins are not well defined on ultrasound. Given the guidance within the Imam reference, and their success in demonstrating immune cell infiltration, a person could have used these ultrasound-guided FNA samples, as taught by Yang et al., in the method of Imam et al. with predictable success of analyzing the lymphocytes and determining the amount of double negative T cells present.
Therefore, the method of the invention is obvious in view of the methods disclosed in the prior art reference, and Claims 1-9, 11-12, and 14-19 are rejected under U.S.C. 103.
(2) Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Imam et al. (2014) in view of Yang et al., as applied to claims 1-9, 11-12, and 14-19 above, and further in view of Razavi et al., 2019.
Applicant traverses this rejection on the grounds that Imam and Razavi both fail to teach or suggest extracting a tissue sample from an area comprising fluid within and adjacent to a thyroid nodule, wherein the area comprises a microenvironment surrounding the thyroid nodule with immune infiltration (pgs. 8-9 of Remarks).
As stated above, there is no explicit definition in the instant specification for the term area comprising a microenvironment “surrounding” the thyroid nodule with immune infiltration. The specification discloses “For the evaluation of the nodule microenvironment, needles are directed to the surroundings of the structural abnormality (i.e., to an area [singular] within and adjacent/intersection to the nodule)” ([00051] emphasis added). Thus, an area (singular) within with the nodule itself is interpreted as comprising a microenvironment surrounding the thyroid nodule, as claimed. Given this interpretation, the teachings of Imam et al. as they pertain to Claims 1, 3-9, 17 and 19 are outlined in the first rejection under 35 USC 103 above. Imam et al. fails to teach methods comprising sequencing RNA in the extracted tissue sample. But, as Applicant has stated in Remarks, “Razavi describes treating part of excised thyroid tumor ‘and adjacent tissues’ in an RNA stabilization reagent for further processing (see page 6).”
The Examiner maintains that it would have been obvious to a person having ordinary skill in the art to combine the teachings of Imam et al. with that of Razavi et al. Explicit motivation is provided wherein Razavi teaches qRT-PCR of GUSB and HPRT1 confers a distinct advantage for diagnosing papillary thyroid carcinoma. Further, the court has held that it is obvious to combine two things, each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) and MPEP 2144.06. Imam et al. teaches the levels of double negative T cells (DNTs) in a thyroid tissue sample, relative to other lymphocytes in the tissue sample, accurately predicts carcinoma over Hashimoto thyroiditis and, Razavi teaches the relative levels of GUSB and HPRT1 accurately predict carcinoma. Thus, it is prima facie obvious to combine these methodologies. Given the guidance in both references, a person having ordinary skill would have been able to combine these teachings with predictable success.
Therefore, the invention of claim 10 is obvious in view of the prior art teachings.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Correspondence
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/STACEY N MACFARLANE/Examiner, Art Unit 1675