DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election of the species of nucleic acids and particularly mutations in nucleic acids in the reply filed on 10 October 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The response states that claims 7, 8 and 12 read on the elected species of nucleic acids. It is agreed that claim 7 encompasses the elected species of nucleic acids since this claim recites “that the indica of cancer comprises a nucleic acid, a protein or a tumor cell.” However, claim 8 does not read on the elected species because this claim requires the combination of both circulating tumor cells and cell-free DNA. The election of species requirement indicated that Applicant was required to elect one of nucleic acids, proteins, or tumor cells or a combination thereof (e.g., the species of the combination of nucleic acids and proteins or the species of the combination of nucleic acids and tumor cells). Applicated elected the species of only nucleic acids and did not elect the combination of nucleic acids and tumor cells (i.e., a combination which includes both cell-free DNA and circulating tumor cells, as recited in claim 8). Note that claim 7 as previously presented recited “wherein indicia of cancer include one or more of a nucleic acid, a protein, or a tumor cell” and in the response of 10 October 2025, Applicant amended claim 7 to recite “wherein the indica of cancer comprise a nucleic acid, a protein or a tumor cell.”
Further, claim 12 recites the species of interleukin- 1, interleukin-6, interleukin- 10, a tumor necrosis factor, matrix metalloproteinase-1, matrix metalloproteinase-2, matrix metalloproteinase-9 or matrix metalloproteinase- 3. Since Applicant did not provide an election of a particular nucleic acid encoding one of the proteins listed in claim 12, claim 12 is considered to be limited to the non-elected species of proteins.
However, as set forth in the restriction requirement, where applicant elects a subcombination and claims thereto are subsequently found allowable, any claim(s) depending from or otherwise requiring all the limitations of the allowable subcombination will be examined for patentability in accordance with 37 CFR 1.104. See MPEP § 821.04(a). Note also that if the elected species is found to be allowable, the examination of a proper Markush claim will be extended to an additional non-elected species. See MPEP 803.02 III.
Claim Status
3. Claims 1-15 are pending.
Claims 8 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-7, 9-11 and 13-15 read on the elected invention and have been examined herein. It is noted that claim 7 encompass the non-elected species of proteins and tumor cells. Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 101
4. 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 1-7, 9-11 and 13-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between an indicia, including a nucleic acid, present in fluid from a lymphatic channel and cancer or metastases (claim 4). Note that the claims are directed to a method for disease diagnosis and recite “detecting indicia of cancer in said fluid.” Claim 13 also recites the correlation between the indicia of cancer and residual disease (i.e., “identifying residual disease based on the detection of indicia of cancer in the fluid”) and claim 15 recites the correlation between the indicia of cancer and disease progression (i.e., “assessing disease progression based on indicia of cancer in the fluid”). As in Mayo Collaborative Services v. Prometheus, the recited correlations / relationships are a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
As stated in MPEP 2106.04(a)(2) III “the "mental processes" abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observations, evaluations, judgments, and opinions.”
Claim 6 recites “assessing relative amounts of said indicia in said lymphatic channel as compared to a lymph node.” The claim does not set forth how the “assessing” or “comparing” (i.e., compared to) steps are accomplished and there is no limiting definition in the specification for “assessing” or “comparing.” As broadly recited, the “assessing” and “comparing” steps may be accomplished mentally, through critical thinking processes. Such “assessing” and “comparing” are thus abstract steps / processes. “Scoring” may also be accomplished verbally, such as by providing a subject / patient with a score. Such verbal communication is also abstract, having no particular concrete or tangible form.
Similarly, claim 9 recites the abstract step of “comparing” the amount of the indicia in the fluid with that in blood.
Claim 10 recites a step of “normalizing” (i.e., “are normalized”) the indicia of cancer to expected amounts in fluid of a patient without cancer. In the absence of a clear definition for “normalizing” in the specification or a recitation in the claims for how “normalizing” is accomplished, the normalizing step may be accomplished by critical thinking processes. Such critical thinking processes constitute an abstract idea.
Regarding claims 13 and 15, the “identifying” and “assessing” are also not defined in the claims as requiring a specific, transformative step and there is no limiting definition for “identifying” and “assessing” in the specification. The broadest reasonable interpretation of the “identifying” and “assessing” steps is that these steps may be accomplished by critical thinking processes. Such “identifying” and “assessing” thereby encompass only an abstract idea / process.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited steps of collecting fluid from a lymphatic channel and detecting an indicia of cancer in the fluid from the lymphatic channel are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
For example, the claims do not practically apply the recited law of nature by including a step of administering a particular drug to the subject to treat a particular disease after the subject has been diagnosed as having the disease or condition based on the presence of the indicia of cancer.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additional non-patent-ineligible steps are recited at a high degree of generality, encompassing any method of collecting fluid from a lymphatic channel, including using any procedure that includes cannulating a lymphatic channel and any conventional method of assaying the obtained fluid for any indicia of cancer, including any nucleic acid. Methods of obtaining lymphatic fluid and assaying the fluid for an indicia, including nucleic acids were well-known, routine and conventional in the prior art. This finding is evidenced by the teachings in the specification at, for example, pages 4 and 6-7 wherein it is disclosed that methods of sequencing, PCR, Western blotting and nucleic acid expression analysis were conventional in the prior art. See also Nowecki et al (British J Dermatology. 159: 597-605; cited in the IDS of 09/19/2025) which teaches methods of collecting lymphatic fluid from a subject and assaying the lymphatic fluid for RNA biomarkers (HTYR, MART1/MelanA and uMAGE) indicative of cancer (e.g., p. 598, col. 2 to p. 599, col. 1 and p. 600, col. 1). Broggi et al (J. Exp. Med. 2019. 218: 1091; cited in the IDS of 09/19/2025) also teaches methods of collecting lymphatic fluid / exudate from lymphatic vessels / channels and assaying the lymphatic fluid to detect miRNAs correlated with melanoma / cancer (e.g., p. 1093 “Lymphatic exudate is enriched in melanoma-associated miRNAs, which are mostly carried in EVs,” p. 1102 col. 2, and p. 1104, col. 2). Callaghan et al (U.S. 20190060546; cited in the IDS of 09/04/2025) also teaches methods of collecting lymphatic fluid from a lymphatic vessel / channel and assaying for biomarkers in the collected lymphatic fluid, such as RNA biomarkers (e.g., para [0007], [0102-0103], and [0110]).
See also MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
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);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
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); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112(b)
5. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4 and 11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 is indefinite over the recitation of “detecting indicia of in-transit metastases.” First, it is unclear as to whether this recitation is intended to require that the detecting occurs in the lymphatic fluid that is collected from the subject or if the detecting may be performed using any other sample from the subject or using any other criteria. Secondly, the specification does not provide a limiting definition for what constitutes “indicia of in-transit metastases” and there is no art recognized definition for this phrase. It is unclear as to what is in-transit and what is encompassed by the indicia. For instance, it is unclear as to whether the indicia is a biomarker or other molecule or is a property or characteristic of the subject. Accordingly, the metes and bounds of the claimed subject matter is unclear.
Claim 11 is indefinite over the recitation of “the fluid is obtained after a cancer treatment.” While the claim previously recites a step of collecting fluid from a lymphatic channel, the claim does not previously recite a step of “obtaining” fluid per se and does not recite a nexus between “obtaining” and “collecting.” Further, the method is one of disease diagnosis of a patient suspected of having cancer. Accordingly, it is not clear as to whether the fluid that is obtained after a cancer treatment is the same as the fluid from the lymphatic channel that is collected from the patient suspected of having cancer or is a different fluid obtained by a different manner / means from a different location / source.
Claim Rejections - 35 USC § 102
6. 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3, 4, 7, 11, 13 and 15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nowecki et al (British J Dermatology. 2008. 159: 597-605; cited in the IDS of 09/19/2025).
Nowecki teaches a method comprising collecting lymphatic fluid from a lymphatic channel / vessel of a patient suspected of having the cancer of melanoma, and detecting mRNAs that are correlated with cancer/melanoma (i.e., an indicia of cancer), in the fluid (see, e.g., abstract, p. 598, col. 2 and p. 600, col. 1).
Nowecki states “One hundred and forty-one patients [macrometastatic group; therapeutic lymph node dissection (TLND)] underwent radical therapeutic lymphadenectomy due to clinically detected (palpable) regional lymph node metastases, which were confirmed pathologically by fine needle aspiration biopsy” (p. 598, col. 2). Further, “(t)he lymph fluid samples (usually 50–100 mL) were collected
24–72 h after the radical lymphadenectomy (CLND or TLND) from routinely used sucking, postoperative drainages” (p. 598, col. 2).
Nowecki teaches that the lymphatic fluid was assayed for 3 biomarkers of melanoma cells (HTYR, MART1 ⁄MelanA and uMAGE) by reverse-transcriptase polymerase chain reaction (RT-PCR) and that the “lymphatic drainage sample was deemed positive for the presence of melanoma cells if at least one melanoma marker
was detected by RT-PCR (p. 600, col. 1).
Regarding claims 3 and 4, the lymphatic channel / vessel from which the lymphatic fluid was obtained in the method of Nowecki is considered to be located between the melanoma / tumor and a lymph node since the lymphatic fluid was collected as drainage fluid after radical lymph node dissection (LND) in patients having metastatic melanoma (p. 598 “Patients and sample collection”). Further, with respect to claim 4, Nowecki states “To summarize, we have demonstrated that the detection of melanoma-characteristic mRNA in lymph fluid after radical node dissection is suggestive of metastatic disease and is related to poor survival.” Thus the mRNA markers that were identified / detected in the method of Nowecki are considered to be an indicia of in-transit metastases.
Regarding claim 7, as discussed above, the method of Nowecki is one that detects mRNA biomarkers - i.e., a nucleic acid - as an indicia of cancer (e.g., p. 600, col. 1 and abstract).
Regarding claim 11, Nowecki teaches that the patients in the study included “(o)ne hundred and forty-one patients [macrometastatic group; therapeutic lymph node dissection (TLND)] underwent radical therapeutic lymphadenectomy due to clinically detected (palpable) regional lymph node metastases (p. 598, col. 2 first para). Accordingly, the method of Nowecki is one in which the fluid from the lymphatic channel / vessel was obtained after the patient was treated with a cancer treatment - i.e., “radical therapeutic lymphadenectomy.”
Regarding claim 13, Nowecki (p. 603, col. 2) states “(a) positive result of the multimarker RT-PCR assay of lymph fluid was demonstrated to be a valuable tool for the prediction of subclinical residual disease, early disease relapse, and shorter survival.” Thereby, the method of Nowecki is one that further comprises identifying residual disease based on the detection of the melanoma mRNA markers in the lymphatic fluid (i.e., “the indicia of cancer in the fluid”).
Regarding claim 15, Nowecki (see Summary) states “(t)he multimarker RT-PCR assay detected melanoma cells in ~32% of LY after LND, which correlated significantly with early melanoma recurrence and shorter survival.” Accordingly, the method of Nowecki is considered to be one that comprises assessing disease progression based on indicia of cancer in the fluid - i.e., based on the presence of the melanoma mRNA markers in the lymphatic fluid. 7. Claim(s) 1, 3-5, and 9 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Han et al (Cytometry. 18 Sept 2020. 99(5): 496-502; cited in the IDS of 09/19/2025).
Han teaches a method comprising collecting lymphatic fluid from a lymphatic vessel / channel of a subject / patient suspected of having cancer / melanoma, and detecting circulating tumor cells (CTCs) that are correlated with the occurrence of the cancer / melanoma (i.e., an indicia of cancer), in the fluid (see, e.g., abstract; Figure 1; and p. 497).
Regarding claims 3-5, Han teaches that the lymph liquid biopsy was collected through sequential cannulations of afferent lymphatic vessel between the primary tumor and its SNL (e.g., p. 498, col. 2; p. 499, col. 2; and Figure 1). For instance, Han (p. 498, col. 1) states “To sample lymph by cannulation of afferent lymphatic vessels, a glass microcannula (custom made in our laboratory), connected with a syringe, was slowly inserted into the vessel..”
Further, with respect to claim 4, Han (p. 499, col. 2) states “By this design, we were able to test the spheroid-forming potential of both afferent and TD L-CTCs as well as blood CTCs in the same mouse at the same time point of disease, and correlate occurrence of stem-like CTCs with size of primary tumor and status of metastasis.” Thus, the CTCs detected in the method of Han are considered to be an indicia of in-transit metastases.
Regarding claim 9, Han further teaches detecting the CTCs (i.e., indicia of cancer) in blood samples from the subject (e.g., p. 498, col. 1 “Blood Collection” and p. 499, col. 2).
Claim Rejections - 35 USC § 103
8. 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 2, 5, 6, 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nowecki et al (British J Dermatology. 2008. 159: 597-605; cited in the IDS of 09/19/2025).
The teachings of Nowecki are presented above.
Regarding claim 2, Nowecki does not teach extracting the lymphatic fluid from the fluid collected from the lymphatic channel. However, Nowecki does teaches that the melanoma cells are present in the lymphatic fluid (p. 598, col. 2). Nowecki also teaches centrifuging the lymphatic drainage fluid samples, incubating the resulting samples with red blood cell-lysing solution; centrifuging a second time and collecting the pellets containing the RNA to be isolated (p. 598, col. 2). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the method of Nowecki by including a step of separating the lymphatic fluid from other materials in the obtained fluid from the lymphatic channel.
Regarding claim 5, Nowecki does not specifically state that the fluid is collected by cannulating the lymphatic channel. However, Nowecki (p. 597, col. 2) states “The lymph fluid samples (usually 50–100 mL) were collected 24–72 h after the radical lymphadenectomy (CLND or TLND) from routinely used sucking, postoperative drainages. Thus, the method of Nowecki involves inserting a tube to collect the drainage fluid. Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the method of Nowecki by collecting the lymphatic fluid from the lymphatic channel by cannulating / inserting a tube into the lymphatic channel since the teachings of Nowecki suggest that this would be an effective means for collecting the lymphatic fluid.
Regarding claim 6, Nowecki does not recite comparing the amount of the melanoma marker nucleic acids from the tumor to that in a lymph node sample. However, since Nowecki teaches that the amount of the melanoma marker nucleic acids in the lymphatic drainage fluid was predictive of metastasis, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have made such a comparison in order to have validated that the results obtained with the lymphatic drainage fluid were accurate for the prediction of metastasis.
Regarding claim 10, Nowecki teaches that the method is one that also analyzed the melanoma RNA markers from the human melanoma cell line MeW151 as a positive control and also from normal and fetal fibroblast lines (p. 599 to p. 600, col. 1). Nowecki (p. 600, col. 1) states “The positive control in each experiment was cDNA from melanoma cell line MeW151, which is known to express each of the three markers.” Nowecki also teaches comparing the results obtained with the RT-PCR assay from a lymphatic drainage fluid sample of a melanoma (cancer) patient with that of other melanoma cancer patients (e.g., p. 600, col. 2 and Figure 1). Nowecki does not specifically teach that the melanoma RNA markers were normalized with respect to the expected amounts in fluid of a patient without cancer. However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have normalized the levels of melanoma RNA markers in the lymphatic fluid of the test patients with that in normal control patients without cancer so as to avoid false positive results and ensure the accuracy of the assay.9. Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nowecki et al (British J Dermatology. 2008. 159: 597-605; cited in the IDS of 09/19/2025) in view of Kulik et al (Melanoma Research. 11: 65-73, 2001).
The teachings of Nowecki are presented above.
Regarding claim 9, Nowecki does not teach comparing the amount of the melanoma RNA markers in the lymphatic fluid to the amount in a blood sample.
However, Kulik (co-authored by Nowecki) teaches methods for detecting melanoma markers MUC-18 and MART-1 in blood samples as indicative of the presence of melanoma cells in blood in patients having melanoma and thereby as indicative of the potential metastasis of a primary melanoma (e.g., abstract and pl 65, col. 2). Kulik also assayed for the presence of melanoma markers MUC-18 and MART-1 in blood samples in healthy subjects. The reference (p. 66, col. 1) reports:
The results presented here indicate that both sets of markers improved the detection of circulating early metastatic melanoma cells. However, because of the presence of the MUC-18 transcript in about 20% of healthy subjects, the TYR/MUC-18 assay is less accurate than the tyrosinase/MART 1 assay.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Nowecki so as to have also assayed for the level of the RNA melanoma markers of HTYR, MART1 ⁄MelanA and uMAGE in a blood sample from the patient and to have compared these results with the level of the RNA melanoma markers in the lymphatic fluid sample. One would have been motivated to have done so in order to have provided additional information regarding the risk of metastasis of the primary melanoma and to have ensured the accuracy of the diagnostic method.10. Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nowecki et al (British J Dermatology. 2008. 159: 597-605; cited in the IDS of 09/19/2025) in view of Suton et al (Int J Oral Maxillofac. Surg. 2012. 41: 413-420).
The teachings of Nowecki are presented above.
Regarding claim 14, Nowecki does not teach that the fluid is collected at or near lymphatic channels in the neck of the patient.
Suton teaches the occurrence of cutaneous melanoma in the neck of patients (Figure 5 and Table 3). Sutton teaches the lymphatic drainage patterns of head and neck cutaneous melanoma through lymphatic channels in the neck and the frequency of metastasis in the patients with head and neck cutaneous melanoma (p. 415-416).
In view of the teachings of Suton of the occurrence of head and neck melanoma and the lymphatic drainage of the head and neck melanomas through the neck and the frequency of metastasis of head and neck cutaneous melanomas, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the method of Nowecki by collecting fluid at or near lymphatic channels of the neck of the patient in those instances in which the patient had a head or neck melanoma.
11. Claim(s) 2, 7, 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han et al (Cytometry. 18 Sept 2020. 99(5): 496-502; cited in the IDS of 09/19/2025).
The teachings of Han are presented above.
Regarding claim 2, Han does not specifically recite that the method comprises extracting the lymphatic fluid from the fluid collected from the lymphatic channel. However, Han teaches the need to separate L-CTCs from endothelial cells present in freshly dissected afferent lymphatic vessels that drain from the primary tumor (p. 499, col. 1). Han (p. 497, col. 1) teaches that this is accomplished by cannulation of afferent lymphatic vessels using a glass microcannula connected with a syringe slowly inserted into the vessel. Accordingly, Han does teach removing the lymph / lymphatic fluid from other fluid or components present in the lymphatic vessel / channel. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the method of Han by including a step of separating the lymphatic fluid from other materials in the obtained fluid from the lymphatic vessel / channel so as to have provided a purified sample containing the CTCs to be assayed as indicative of cancer metastasis.
Regarding claim 7, Han exemplifies methods of detecting the indicia of cancer of CTCs in the lymphatic fluid. Han does not exemplify a method of detecting a nucleic acid as the indicia of cancer.
However, Han (p. 501, col. 2 final para) states that “extension of using lymph liquid biopsy to detect other markers (e.g., circulating tumor-related DNA and miRNA) in metastatic tumors would be the foundation for discovering lymphatic-related mechanisms of metastasis and development of novel tumor biomarkers.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have applied the method of Han to the detection of circulating tumor DNA or miRNA in the lymphatic fluid because Han teaches that these would also be effective markers for the detection of metastasis.
Regarding claim 10, Han does not specifically teach that quantity of the CTCs were normalized with respect to the expected amounts in fluid of a patient without cancer. However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have normalized the levels of CTCs in the lymphatic fluid of the test patients with that in normal control patients without cancer so as to avoid false positive results and ensure the accuracy of the assay.12. Claim(s) 11, 13 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han et al (Cytometry. 18 Sept 2020. 99(5): 496-502; cited in the IDS of 09/19/2025) in view of Wang et al (U.S. 20180252722; cited in the IDS of 09/19/2025).
The teachings of Han are presented above.
Han doesn’t teach that the fluid from the lymphatic channel is collected after a cancer treatment (claim 11) or is indicative of residual disease (claim 13) or progression of cancer (claim 15).
However, Wang teaches methods for detecting circulating tumor cells (CTCs) present in lymphatic fluid as indicative of cancer in a subject or cancer metastasis (para [0009], and [0014-0016]). Han (para [0032]) states:
“the present invention provides a method of making prognostic prediction of a cancer treatment in a patient, comprising a) counting CTCs in a patient's blood sample or lymphatic fluid sample at different times during or after the cancer treatment using the method described herein; and b) using a increasing and decreasing count of CTCs in patient's sample as indicative of a poor and good prognosis, respectively.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Han so as to have assayed for CTCs in the lymphatic fluid after a cancer treatment (and prior to treatment), as taught by Wang. One would have been motivated to have done so for the advantage set forth by Wang that such assays provide information regarding the, disease progression and the prognosis of the patient. Regarding claim 13, modification of the method of Han as set forth above would have also provided information regarding the presence of residual disease, since as discussed by Wang, the presence of the CTCs carrying tumor-specific markers indicates the presence of cancer in the patient (e.g., para [0009], [0014-0016] and claim 17).
13. Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Han et al (Cytometry. 18 Sept 2020. 99(5): 496-502; cited in the IDS of 09/19/2025) in view of Suton et al (Int J Oral Maxillofac. Surg. 2012. 41: 413-420).
The teachings of Han are presented above.
Regarding claim 14, Han teaches that the subjects had ear melanomas / tumors (P. 499, col. 2). Han does not teach that the fluid is collected at or near lymphatic channels in the neck of the subject.
Suton teaches the occurrence of cutaneous melanoma in the neck of patients (Figure 5 and Table 3). Sutton teaches the lymphatic drainage patterns of head and neck cutaneous melanoma through lymphatic channels in the neck and the frequency of metastasis in the patients with head and neck cutaneous melanoma (p. 415-416).
In view of the teachings of Suton of the occurrence of head and neck melanoma and the lymphatic drainage of the head and neck melanomas through the neck and the frequency of metastasis of head and neck cutaneous melanomas, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the method of Han by collecting fluid at or near lymphatic channels of the neck of a subject in those instances in which the subject had a head or neck melanoma.
Rejections - Double Patenting
14. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-7, 9-11 and 13-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of copending Application No. 17/947,861 (reference application) in view of Lau, D. (U.S. 2020/00258601). Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims and the claims of ‘861 are both inclusive of methods comprising the steps of obtaining lymphatic fluid from a lymphatic channel (also referred to in the claims of ‘861 as drain fluid) and assaying the fluid for a marker of cancer, including a nucleic acid marker of cancer or a tumor cell (e.g., claims 1, 6, 7, 11, 12 and 19). Note that the specification of ‘861 defines a drain fluid as including a lymphatic fluid (e.g., para [0007]).
Regarding present claim 2, claim 23 of ‘861 recites that the method is one in which lymphatic fluid is separated from the drain fluid (i.e., fluid in the lymphatic channel).
Regarding claim 3, since the claims of ‘861 include methods of collecting lymphatic fluid from a lymphatic channel to diagnose cancer or cancer metastasis and claim 31 of ‘861 recites “accessing fluid that exists between a tumor and a lymphatic channel; a lymphatic channel and a lymph node,” it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the methods claimed in ‘861 by collecting fluid from a lymphatic channel is located between a tumor and a first lymph node such that the lymphatic channel drains from the tumor.
Regarding claim 4, the claims of ‘861 include detecting a marker of metastatic disease and thereby an indicia of in-transit metastases.
Regarding present claim 5, claim 12 of ‘861 recites that the lymphatic fluid is obtained by catheterization of the lymphatic channel. Accordingly, the claims of ‘861 suggest that the obtaining step comprises cannulating the lymphatic channel.
Regarding present claim 6, the claims of ‘861 (e.g., claim 21) also encompass detecting and comparing the amount of the cancer biomarkers, including circulating tumor DNA biomarkers, to the amount of the cancer biomarkers in lymph nodes.
Regarding present claim 9, the claims of ‘861 include detecting the biomarker in a blood sample (e.g., claim 17 and 25).
Regarding present claim 10, the claims of ‘861 do not recite comparing he amount of the biomarker of cancer, including cell-free DNA, in the lymphatic fluid from the subject to that in a sample from a healthy subject. However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have compared the biomarkers present in the lymphatic fluid of the subject to that of a healthy control in order to have determined if there were differences in the quantity of the cancer biomarkers in the two sample types.
Regarding present claims 11, 13 and 15, the claims of ‘861 include obtaining the fluid sample at a first and second time point and assessing disease progression (claim 1) as well as determining the stage of cancer (e.g., claims 25 and 31). Accordingly, the claims of ‘861 in combination suggest the presently claimed methods wherein the fluid sample is collected after the subject has been treated for cancer and determining cancer progression and/or residual cancer.
Regarding present claim 14, although the claims of ‘861 do not recite that the lymphatic channel is in the neck of the subject, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the claimed method so as to have specifically obtained the lymphatic fluid from a lymphatic channel in the neck in those instances in which the cancer was associated with the neck of the subject.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
13. Claims 1-2, 7, 9, 10 and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable claims 1-11 and 13-20 of copending Application No. 17/948,760 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims and the claims of ‘760 are both inclusive of methods of diagnosing cancer comprising the steps of obtaining fluid from a lymphatic duct or thoracic duct (i.e., a lymphatic channel) of a subject and detecting a biomarker of cancer in the fluid.
Regarding claim 2, the claims of ‘760 (e.g., claim 10) included a step of separating the lymphatic fluid from the obtained drain fluid.
Regarding present claim 7 and 9, the claims of ‘760 (e.g., claims 5, 6 an d9) also encompass detecting and comparing the amount of the cancer biomarkers, including circulating tumor DNA biomarkers, to the amount of the cancer biomarkers in a blood sample from the subject.
Regarding present claim 10, the claims of ‘760 do not recite comparing he amount of the biomarker of cancer, including cell-free DNA, in the lymphatic fluid from the subject to that in a sample from a healthy subject. However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have compared the biomarkers present in the in lymphatic fluid of the subject to that of a healthy control in order to have determined if there were differences in the quantity of the cancer biomarkers in the two sample types.
Regarding present claim 11, the claims of ‘760 (e.g., claims 1 and 13) encompass methods wherein the subject has been treated with a surgery, including a resection, dissection or excision and thereby the lymphatic fluid sample is obtained after a cancer treatment.
Regarding present claim 14, the claims of ‘760 recite obtaining the lymphatic fluid from the thoracic duct (e.g., claims 1, 16 and 21) and thereby from a lymphatic channel in the neck of the subject.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
14. Claims 3-5, and 6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 13-20 of copending Application No. 17/948,760 (reference application) in view of Nowecki et al (British J Dermatology. 2008. 159: 597-605; cited in the IDS of 09/19/2025).
The claims of ‘760 are discussed above.
Regarding present claims 3 and 4, the claims of ‘760 do not recite that the lymphatic channel is located between a tumor and a first lymph node.
However, Nowecki teaches a method comprising collecting lymphatic fluid from a lymphatic channel / vessel of a patient suspected of having the cancer of melanoma, and detecting mRNAs that are correlated with cancer/melanoma (i.e., an indicia of cancer), in the fluid (see, e.g., abstract, p. 598, col. 2 and p. 600, col. 1).The lymphatic channel / vessel from which the lymphatic fluid was obtained in the method of Nowecki is considered to be located between the melanoma / tumor and a lymph node since the lymphatic fluid was collected as drainage fluid after radical lymph node dissection (LND) in patients having metastatic melanoma (p. 598 “Patients and sample collection”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically performed the method claimed in ‘760 by collecting fluid from a lymphatic channel located between a tumor and a first lymph node because, as taught by Nowecki, this lymphatic channel contains biomarkers from the cancer cells. Further, with respect to claim 4, Nowecki states “To summarize, we have demonstrated that the detection of melanoma-characteristic mRNA in lymph fluid after radical node dissection is suggestive of metastatic disease and is related to poor survival.” Thus the detection of the biomarkers in the lymphatic fluid in the method claimed in ‘760 is considered to be an indicia of in-transit metastases.
Regarding present claim 5, the claims of ‘760 do not recite that the fluid is collected by cannulating the lymphatic channel. However, Nowecki (p. 597, col. 2) teaches that “The lymph fluid samples (usually 50–100 mL) were collected 24–72 h after the radical lymphadenectomy (CLND or TLND) from routinely used sucking, postoperative drainages.” Thus, Nowecki teaches inserting a tube to collect the drainage fluid. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the method claimed in ‘760 by collecting the lymphatic fluid from the lymphatic channel by cannulating / inserting a tube into the lymphatic channel since the teachings of Nowecki suggest that this would be an effective means for collecting lymphatic fluid.
Regarding present claim 6, the claims of ‘760 do not recite comparing the amount of the melanoma marker nucleic acids from the tumor to that in a lymph node sample. However, Nowecki teaches that the amount of the melanoma marker nucleic acids in the lymphatic drainage fluid was predictive of metastasis to a lymph node. Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘760 so as to have compared the amount of a biomarker in the lymphatic drainage with that at a lymph node in order to have determined if the results obtained with the lymphatic drainage fluid were accurate for the prediction of metastasis.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
15. Claims 13 and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 13-20 of copending Application No. 17/948,760 (reference application) in view of Wang et al (U.S. 20180252722; cited in the IDS of 09/19/2025).
The claims of ‘760 are discussed above.
Regarding present claims 13 and 15, the claims of ‘760 do not specifically recite that the method is one for detecting residual cancer or the progression of cancer. However, the claims of ‘760 are directed to a method of disease diagnosis and include the step of detecting a cancer biomarker (e.g., claim 1), including DNA from a tumor cell or from cell-free tumor DNA in the lymphatic fluid (claim 9).
Further, Wang teaches methods for detecting circulating tumor cells (CTCs) present in lymphatic fluid as indicative of cancer in a subject or cancer metastasis (para [0009], and [0014-0016]). Han (para [0032]) states:
“the present invention provides a method of making prognostic prediction of a cancer treatment in a patient, comprising a) counting CTCs in a patient's blood sample or lymphatic fluid sample at different times during or after the cancer treatment using the method described herein; and b) using a increasing and decreasing count of CTCs in patient's sample as indicative of a poor and good prognosis, respectively.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘760 so as to have assayed for circulating tumor cells in the lymphatic fluid after a cancer treatment (and prior to treatment), as taught by Wang. One would have been motivated to have done so for the advantage set forth by Wang that such assays provide information regarding the, disease progression and the prognosis of the patient. Regarding claim 13, modification of the method claimed in ‘760 as set forth above would have also provided information regarding the presence of residual disease, since as discussed by Wang, the presence of the CTCs carrying tumor-specific markers indicates the presence of cancer in the patient (e.g., para [0009], [0014-0016] and claim 17).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
16. Claims 1-7, 9-11 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12152280 in view of Nowecki et al (British J Dermatology. 2008. 159: 597-605; cited in the IDS of 09/19/2025).
. Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims and the claims of ‘280 are both inclusive of methods comprising collecting lymphatic fluid (drain fluid in claim 1 of ‘280) and assaying the lymphatic fluid for an indicia of cancer (i.e., RNA from a tumor cell in claim 1 of ‘280). See claim 14 of ‘280 which recites “further comprising separating a lymphatic fluid from the drain fluid, and wherein the single tumor cell is obtained from the separated lymphatic fluid.” Accordingly, the drain fluid that is assayed for the indicia of cancer is lymphatic fluid. The claims of ‘280 do not specify that the lymphatic fluid is obtained from a lymphatic channel. However, claims 8-10 of ‘280 encompass methods wherein the drain fluid / lymphatic fluid is collected using a catheter or drain port near a surgical site. Further, when read in light of the specification of ‘280, it is clear that the lymphatic fluid is to be collected from a lymphatic vessel using the catheter or drain port.
Additionally, Nowecki teaches a method comprising collecting lymphatic fluid from a lymphatic channel / vessel of a patient suspected of having the cancer of melanoma, and detecting mRNAs that are correlated with cancer/melanoma (i.e., an indicia of cancer), in the fluid (see, e.g., abstract, p. 598, col. 2 and p. 600, col. 1).The lymphatic channel / vessel from which the lymphatic fluid was obtained in the method of Nowecki is considered to be located between the melanoma / tumor and a lymph node since the lymphatic fluid was collected as drainage fluid after radical lymph node dissection (LND) in patients having metastatic melanoma (p. 598 “Patients and sample collection”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically performed the method claimed in ‘280 by collecting fluid from a lymphatic channel located between a tumor and a first lymph node because, as taught by Nowecki, this lymphatic channel contains biomarkers from the cancer cells. Further, with respect to claim 4, Nowecki states “To summarize, we have demonstrated that the detection of melanoma-characteristic mRNA in lymph fluid after radical node dissection is suggestive of metastatic disease and is related to poor survival.” Thus the detection of the biomarkers in the lymphatic fluid in the method claimed in ‘280 is considered to be an indicia of in-transit metastases.
Regarding present claim 5, the claims of ‘280 do not recite that the fluid is collected by cannulating the lymphatic channel. However, Nowecki (p. 597, col. 2) teaches that “The lymph fluid samples (usually 50–100 mL) were collected 24–72 h after the radical lymphadenectomy (CLND or TLND) from routinely used sucking, postoperative drainages.” Thus, Nowecki teaches inserting a tube to collect the drainage fluid. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the method claimed in ‘280 by collecting the lymphatic fluid from the lymphatic channel by cannulating / inserting a tube into the lymphatic channel since the teachings of Nowecki suggest that this would be an effective means for collecting lymphatic fluid.
Regarding present claim 6, the claims of ‘280 do not recite comparing the amount of the cancer biomarker from the tumor to that in a lymph node sample. However, Nowecki teaches that the amount of the melanoma marker nucleic acids in the lymphatic drainage fluid was predictive of metastasis to a lymph node. Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘280 so as to have compared the amount of a biomarker in the lymphatic drainage with that at a lymph node in order to have determined if the results obtained with the lymphatic drainage fluid were accurate for the prediction of metastasis.
17. Claims 13 and 15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12152280 in view of Nowecki et al (British J Dermatology. 2008. 159: 597-605; cited in the IDS of 09/19/2025) and further in view of Wang et al (U.S. 20180252722; cited in the IDS of 09/19/2025).
The claims of ‘280 and the teachings of Nowecki are presented above.
Regarding present claims 13 and 15, the claims of ‘280 do not specifically recite that the method is one for detecting residual cancer or the progression of cancer.
However, Wang teaches methods for detecting circulating tumor cells (CTCs) present in lymphatic fluid as indicative of cancer in a subject or cancer metastasis (para [0009], and [0014-0016]). Han (para [0032]) states:
“the present invention provides a method of making prognostic prediction of a cancer treatment in a patient, comprising a) counting CTCs in a patient's blood sample or lymphatic fluid sample at different times during or after the cancer treatment using the method described herein; and b) using a increasing and decreasing count of CTCs in patient's sample as indicative of a poor and good prognosis, respectively.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘280 so as to have assayed for circulating tumor cells in the lymphatic fluid after a cancer treatment (and prior to treatment), as taught by Wang. One would have been motivated to have done so for the advantage set forth by Wang that such assays provide information regarding the, disease progression and the prognosis of the patient. Regarding claim 13, modification of the method claimed in ‘280 as set forth above would have also provided information regarding the presence of residual disease, since as discussed by Wang, the presence of the CTCs carrying tumor-specific markers indicates the presence of cancer in the patient (e.g., para [0009], [0014-0016] and claim 17).
18. Claims 1-7, 9-11 and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-32 of copending Application No. 18/958,592 (reference application) in view of Nowecki et al (British J Dermatology. 2008. 159: 597-605; cited in the IDS of 09/19/2025).
.Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims and the claims of ‘592 are both inclusive of methods comprising collecting lymphatic fluid (drain fluid in claim 1 of ‘592; lymphatic fluid in claim 17) and assaying the lymphatic fluid for an indicia of cancer (e.g.., circulating tumor DNA in claim 15; nucleic acid in claim 20; a cancer cell in claim 21) See also claim 18 of ‘592 which recites “further comprising separating the lymphatic fluid from the plurality of drain fluid samples.” Accordingly, the drain fluid that is assayed for the indicia of cancer is lymphatic fluid. The claims of ‘592 do not specify that the lymphatic fluid is obtained from a lymphatic channel.
However, Nowecki teaches a method comprising collecting lymphatic fluid from a lymphatic channel / vessel of a patient suspected of having the cancer of melanoma, and detecting mRNAs that are correlated with cancer/melanoma (i.e., an indicia of cancer), in the fluid (see, e.g., abstract, p. 598, col. 2 and p. 600, col. 1).The lymphatic channel / vessel from which the lymphatic fluid was obtained in the method of Nowecki is considered to be located between the melanoma / tumor and a lymph node since the lymphatic fluid was collected as drainage fluid after radical lymph node dissection (LND) in patients having metastatic melanoma (p. 598 “Patients and sample collection”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically performed the method claimed in ‘592 by collecting fluid from a lymphatic channel located between a tumor and a first lymph node because, as taught by Nowecki, this lymphatic channel contains biomarkers from the cancer cells. Further, with respect to claim 4, Nowecki states “To summarize, we have demonstrated that the detection of melanoma-characteristic mRNA in lymph fluid after radical node dissection is suggestive of metastatic disease and is related to poor survival.” Thus the detection of the biomarkers in the lymphatic fluid in the method claimed in ‘592 is considered to be an indicia of in-transit metastases.
Regarding present claim 5, the claims of ‘592 do not recite that the fluid is collected by cannulating the lymphatic channel. However, Nowecki (p. 597, col. 2) teaches that “The lymph fluid samples (usually 50–100 mL) were collected 24–72 h after the radical lymphadenectomy (CLND or TLND) from routinely used sucking, postoperative drainages.” Thus, Nowecki teaches inserting a tube to collect the drainage fluid. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the method claimed in ‘592 by collecting the lymphatic fluid from the lymphatic channel by cannulating / inserting a tube into the lymphatic channel since the teachings of Nowecki suggest that this would be an effective means for collecting lymphatic fluid.
Regarding present claim 6, the claims of ‘592 do not recite comparing the amount of the cancer biomarker from the tumor to that in a lymph node sample. However, Nowecki teaches that the amount of the melanoma marker nucleic acids in the lymphatic drainage fluid was predictive of metastasis to a lymph node. Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘592 so as to have compared the amount of a biomarker in the lymphatic drainage with that at a lymph node in order to have determined if the results obtained with the lymphatic drainage fluid were accurate for the prediction of metastasis.
Regarding present claim 11, the claims of ‘592 encompass methods wherein the subject has been treated - e.g., claim 15 recites “obtaining a plurality of drain fluid samples during a treatment.” The claims of ‘592 also encompass methods wherein the subject has cancer (claim 23). Accordingly, the claimed method of ‘592 is one in which the lymphatic fluid sample is obtained after a cancer treatment.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
19. Claims 13 and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-32 of copending Application No. 18/958,592 (reference application) in view of Nowecki et al (British J Dermatology. 2008. 159: 597-605; cited in the IDS of 09/19/2025)and further in view of Wang et al (U.S. 20180252722; cited in the IDS of 09/19/2025).
The claims of ‘592 and the teachings of Nowecki are presented above.
Regarding present claims 13 and 15, the claims of ‘592 do not specifically recite that the method is one for detecting residual cancer or the progression of cancer.
However, Wang teaches methods for detecting circulating tumor cells (CTCs) present in lymphatic fluid as indicative of cancer in a subject or cancer metastasis (para [0009], and [0014-0016]). Han (para [0032]) states:
“the present invention provides a method of making prognostic prediction of a cancer treatment in a patient, comprising a) counting CTCs in a patient's blood sample or lymphatic fluid sample at different times during or after the cancer treatment using the method described herein; and b) using a increasing and decreasing count of CTCs in patient's sample as indicative of a poor and good prognosis, respectively.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘592 so as to have assayed for circulating tumor cells in the lymphatic fluid after a cancer treatment (and prior to treatment), as taught by Wang. One would have been motivated to have done so for the advantage set forth by Wang that such assays provide information regarding the, disease progression and the prognosis of the patient. Regarding claim 13, modification of the method claimed in ‘592 as set forth above would have also provided information regarding the presence of residual disease, since as discussed by Wang, the presence of the CTCs carrying tumor-specific markers indicates the presence of cancer in the patient (e.g., para [0009], [0014-0016] and claim 17).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached on 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CARLA J MYERS/Primary Examiner, Art Unit 1682