19DETAILED 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11 May 2026 has been entered.
Response to Amendment
Claims 13 and 20-21 were previously cancelled. Claims 1, 11, and 17 have been amended as requested in the amendment filed on 11 May 2026. 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 5-7 of Remarks filed 11 May 2025, Applicant traverses the rejection on the following grounds. Applicant argues that, as currently amended, claims 1, 11 and 17 have been amended to recite the method steps for extracting “comprises inserting a needle through skin of the patient under direct imaging guidance, advancing the needle to an interface of the thyroid nodule and solid mass-infiltrate, and aspirating the tissue sample” and in view of these amendments the rejection is untenable because the claims are not directed to a judicial exception itself. “Rather, they mandate physically obtaining a specimen from a particular microenvironment and performing cell-type-specific quantification” (pg. 5 last line). Applicant asserts the “human-performed medical procedure” is a concrete, physical and transformative step not a mental process. Further, Applicant argues that the steps integrate any judicial exceptions into a practical application because it requires a specific manner of sample acquisition.
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 still recite judicially excepted subject matter (analyzing and determining an amount). Thus, the claims still recite at least one judicial exception (STEP 2A, Prong One: YES).
The newly added steps/elements does not appear to integrate those judicial exceptions into a practical application because the additional steps do not present any of the considerations set forth in MPEP 2106.05(a-c), (e) and (h) that demonstrate integration. There is no evidence that the additional steps/elements provide an improvement within 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 described in MPEP § 2106.04(d)(2). 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), 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 recite more well-understood, routine, conventional activities previously known to the industry. The steps/elements recited in addition to the judicially exception(s) must amount to significantly more than the judicial exception(s) itself. The newly added limitation recites wherein, “extracting comprises inserting a needle through skin of the patient under direct imaging guidance, advancing the needle to an interface of the thyroid nodule and solid mass-infiltrate, and aspirating the tissue sample” and must be evaluated for whether it amounts to significantly more than what was well-understood, routine and conventional in the art at the time of filing.
The following prior art teaches it was well-established to sample the areas of jagged edges, lobulated borders, and curved borders at the margins of thyroid nodules (Siebert et al., AJR 2018; 210:860–865). The authors state: (Abstract) “The diagnostic performance of jagged edges in papillary carcinoma of the thyroid was 67.4% sensitive and 78.3% specific (odds ratio, 7.44; p < 0.001) for malignancy. Jagged edges correlated with infiltrative variant expansion at slide review. Lobulated borders had sensitivity of 76.1% and specificity of 60.9% for papillary carcinoma (odds ratio, 4.95; p =0.001) for malignancy. Curved borders were not a significant predictor of papillary carcinoma. CONCLUSION. Jagged edges and lobulated borders of thyroid nodule margins are statistically significant predictors of papillary carcinoma of the thyroid. Jagged edges correlate with in-filtrative-type expansion and may be useful predictors of more aggressive papillary carcinomas.” Thus, the prior art teaches it was well-understood that “review of the surgical specimens revealed multiple cases of invasive borders into the thyroid parenchyma, consistent with infiltrative-type margins (Fig. 5B). The lobulated-border finding had greater sensitivity (76.1%; 95% CI, 61.2–87.4%) than the jagged-edge finding and lower specific-ity (60.9%; 95% CI, 45.4–74.9%) for predicting papillary carcinoma (pg. 862, third column, first paragraph). The Siebert reference concludes: “We found examination of thyroid nodule margins for jagged edges and lobulations to be helpful in predicting risk of the presence of potential papillary carcinoma. Pathologic association with the infiltrative type of expansion merits further study, but nodule mar-gins appear to be a promising tool in predicting more aggressive thyroid cancer behavior” (pg. 864, last paragraph). Thus, the steps do not amount to significantly more than what was routine at the time of filing.
For all of these reasons, the claims as a whole are directed to a 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.
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 in view of Siebert et al., (2017) cited above.
On pages 7-8 of Remarks filed on 11 May 2026, Applicant asserts that neither Imam nor Yang prior art references teach the new limitation of targeting an interface of the thyroid nodule and solid mass-infiltrate.
While these arguments have been reviewed in full, they are not persuasive to overcome the rejection of record. Since this is a new limitation, it warrants further search and application of new prior art. As such the Siebert prior art has been cited.
In Remarks Applicant states Imam describes sampling intramodular tissue from resected sections not in vivo interface tissue. This is not persuasive because a reference serves as prior art for all that it teaches (MPEP 2158 citing Beckman Instruments v. LKB Produkter AB, 892 F.2d 1547, 1551, 13 USPQ2d 1301, 1304 (Fed. Cir. 1989) "Even if a reference discloses an inoperative device, it is prior art for all that it teaches.") Imam et al. discloses the patients referred for thyroid surgery included those with positive or suspicious cytology for malignancy on fine needle aspiration (FNA) and those with compressive symptoms (such as dysphagia, shortness of breath or hoarseness). Therefore, in vivo FNA was known in the art prior to filing and routinely used to identify the patients referred for thyroid surgery in the clinical study. Imam et al. teach the resected samples demonstrate immune cell infiltration. Specifically, the authors analyze the tissue samples for macrophages and NK cells, and teach samples are 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.
While Imam explicitly suggests FNA it does not teach determination of double negative T cells from FNA samples. Applicant argues the Yang reference does not remedy this deficiency because Yang only describes ultrasound morphology. Reference to Yang is mott in view of current claim limitations.
The Siebert et al. prior art is relied upon as teaching (Abstract): “The diagnostic performance of jagged edges in papillary carcinoma of the thyroid was 67.4% sensitive and 78.3% specific (odds ratio, 7.44; p < 0.001) for malignancy. Jagged edges correlated with infiltrative variant expansion at slide review. Lobulated borders had sensitivity of 76.1% and specificity of 60.9% for papillary carcinoma (odds ratio, 4.95; p = 0.001) for malignancy. Curved borders were not a significant predictor of papillary carcinoma.” Siebert et al. state: “the sonographic features of thyroid nodules have been well studied and in combination with size can facilitate more informed selection for further evaluation with fine-needle aspiration biopsy” (pg. 860, first paragraph). It should be noted that the terms ultra-sound guided biopsy and fine-needle aspiration biopsy are used interchangeably in the art (see attached search notes from Radiologyinfo.org and Jefferson Radiology). Siebert concludes: “Jagged edges and lobulated borders of thyroid nodule margins are statistically significant predictors of papillary carcinoma of the thyroid. Jagged edges correlate with infiltrative-type expansion and may be useful predictors of more aggressive papillary carcinomas.” Siebert et al. further corroborated this finding by looking at photomicrographs of the biopsied nodules after total thyroidectomy (Figure 5B and C).
Based upon the teachings of the references, it would have been obvious to a person having ordinary skill in the art, before the effective filing date of the application, to use ultrasound-guided FNA tissue samples from an interface of the thyroid nodule and solid mass-infiltrate, in the double negative staining methods of Imam. FNA was the standard means for biopsy in the field of thyroid cancer, as both references disclose. Motivation to specifically look at the margins (a.k.a. “an interface of the thyroid nodule and solid-mass infiltrate” of the claim) is explicit in Siebert et al. wherein it evaluated nodules with high-resolution ultrasound (equivalent to “direct imaging guidance” of the instant claim) and ultrasound-guided FNA biopsy demostrated jagged edges and lobulated borders of thyroid nodule margins were statistically significant predictors of papillary carcinoma of the thyroid. Jagged edges correlate with infiltrative-type expansion and may be useful predictors of more aggressive papillary carcinomas (Abstract). In KSR International Co. v. Teleflex, Inc., the Supreme Court has stated that where there is a “pressure to solve a problem and a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense” (KSR International Co. v. Teleflex, Inc. 127 S. Ct. 1727, 82 USPQ2d 1385, Supreme Court, April 30, 2007). In the instant case, the problem to be solved is diagnosis of thyroid carcinoma and the art demonstrates that there are a finite number of features observed on ultrasound (US) that correlate with carcinoma; and that jagged edges are correlated with infiltrative-type expansion and may be useful predictors of more aggressive papillary carcinomas. These jagged edge samples could be used in the methods of Imam since infiltrative double negative T cells are also significantly elevated in papillary thyroid cancer (PTC). The biopsy samples as disclosed by Siebert could have been substituted for the samples in the methods of Imam et al. and subjected to the analysis for double negative T cells with predictable success. Further motivation to use FNA instead of resected tissue is because it is much less invasive a procedure than surgical resection used by Imam. A person having ordinary skill would have been able to predictably use the jagged edge samples, as taught by Siebert et al. to determine an amount of double negative T cells present in the samples since both references equate jagged edges and the presence of negative T cells with the immune cell infiltration associated with PTC.
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 Imam and Siebert 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 the newly added limitation “wherein the extracting comprises inserting a needle through skin of the patient under direct imaging guidance, advancing the needle to an interface of the thyroid nodule and solid mass-infiltrate, and aspirating the tissue sample”.
The rejection of Claims 1-9, 11-12, and 14-19 is outlined in the rejection under 35 USC 103 above. Neither Imam et al. nor Siebert et al. 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 elements 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 indicate PTC; Siebert teach jagged edges seen on ultrasound correlate with the cytological infiltration that also correlates with a diagnosis of PTC; 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 since each of the elements are merely performing the same function that they did in the separate references.
Therefore, the invention of claim 10 is obvious in view of the prior art teachings.
Conclusion
No claim is allowed.
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/STACEY N MACFARLANE/Examiner, Art Unit 1675
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