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 .2. This action is in response to the amendment filed on 28 May 2026. Applicant's arguments and amendments to the claims have been fully considered but do not place the application in condition for allowance. All rejections not reiterated herein are hereby withdrawn.
In particular, the previous rejection of claim 4 under 35 U.S.C 112(b) has been obviated by the cancellation of claim 4 and the previous rejection of claim 11 under 35 U.S.C. 112(b) has been obviated by the amendment to claim 11. The previous rejection of the claims under 35 U.S.C. 102 as anticipated by Han et al and under 35 U.S.C. 103 as obvious over Han et al have been obviated by the amendments to the claims.
Claim Status
3. Claims 1-3, 5 and 7-22 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Claims 8 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.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 1-3, 5, 7, 9-11 and 13-22 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.
Maintained / Modified 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 1-3, 5, 7, 9-11 and 13-22 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, as well as in a lymph node, and cancer or cancer progression, including metastases. Note that the claims are directed to a method for cancer 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 claims 15 and 19 recite 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.”
The claims recite “assessing relative amounts of said indicia in said lymphatic channel as compared to a lymph node.” The claims do 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. “Accessing” 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.
Regarding new claim 22, this claim requires comparing measured amounts of the indicia “from assays performed.” This claim does not require performing the assays as part of the claimed method. Again, this assessing step can also be accomplished by reading information in a report or database required measured levels of the indicia and then mentally comparing these levels. As such, the assessing step in claim 22 is an abstract idea.
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, 15, and 19, 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 cancer after the subject has been diagnosed as having the cancer 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.Response to Remarks:
The response argues that the claims are not directed to a judicial exception. The response states: “As amended, independent claim 1 is directed to a human-engineered diagnostic method that requires (i) collecting fluid from a lymphatic channel, (ii) detecting indicia of cancer in that fluid, and (iii) assessing relative amounts of the indicia in lymphatic channel fluid and in a lymph node.
This claim does not merely recite a biological correlation. Rather, the claim defines a multi-sample, anatomically grounded diagnostic workflow that requires obtaining and measuring indicia from distinct physical compartments of the body and assessing those measured amounts to determine disease state.”
These arguments have been fully considered but are not persuasive. For the reasons discussed in detail in the rejection, the claims do recite the natural correlation between the indicia and cancer (e.g., “an indicia of cancer” and “A method for cancer diagnosis” by “assessing relative amounts of said indicia in said fluid and in a lymph node.” The claims also recite the judicial exception of abstract steps / ideas - i.e., the “assessing,” “comparing,” “normalizing,” and “identifying.”
Additionally, regarding Applicant’s argument pertaining to “directed to,” MPEP 2106.04II states:
1. Prong One
Prong One asks does the claim recite an abstract idea, law of nature, or natural phenomenon? In Prong One examiners evaluate whether the claim recites a judicial exception, i.e. whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim. While the terms "set forth" and "described" are thus both equated with "recite", their different language is intended to indicate that there are two ways in which an exception can be recited in a claim….
If the claim recites a judicial exception (i.e., an abstract idea enumerated in MPEP § 2106.04(a), a law of nature, or a natural phenomenon), the claim requires further analysis in Prong Two.” (Emphasis added).
The response argues that “the present claims contain concrete actions performed on physical biological samples” and points to the steps in claim 1 of collecting the lymphatic channel fluid, detecting the indicia of cancer in the fluid and “assessing measured amounts of indicia from two different biological specimens, lymphatic channel fluid and in a lymph node.”
These arguments have also been fully considered but are not persuasive. First, it is noted that the assessing step is not a “concrete action.” Rather, as set forth above, this step is the judicial exception of an abstract idea / process since this step can be performed mentally by comparing the step that can be performed mentally
Further, while the claim does recite “concrete” steps of collecting a fluid from a lymphatic channel and detecting an indicia of cancer in the fluid, these steps do not negate the fact that the claims still recite the judicial exceptions of a natural phenomenon (the natural correlation) and abstract ideas / processes. See, MPEP 2106.05(c) which states:
“It is noted that while the transformation of an article is an important clue, it is not a stand-alone test for eligibility.” It goes on to state “if a claim fails the Alice/Mayo test (i.e., is directed to an exception at Step 2A and does not amount to significantly more than the exception in Step 2B), then the claim is ineligible even if it passes the M-or-T test.”
Herein, the claims fail the Alice/Mayo test for the reasons discussed in detail above.
The response argues that the claims are distinct over the claims in Cleveland Clinic, which observed correlations in conventional blood samples, because the present claims “require acquiring and analyzing a non-routine biological substrate, lymphatic channel fluid, and performing a compartment-to-compartment assessment relative to a lymph node.”
This argument is also not persuasive because the sample in which the indicia of cancer is detected is part of the natural phenomenon. That is, the occurrence of the indicia of cancer in lymphatic fluid and lymph node tissue is a natural phenomenon. Further, the correlation between the amount of the indicia in the lymphatic fluid relative to the amount in a lymph node and the occurrence of cancer and progression of cancer / metastasis of cancer is a natural phenomenon.
The response argues that the additionally recited steps in the claims “define a specific diagnostic workflow” and practically apply the judicial exception.
These arguments are not persuasive. The additionally recited, non-patent-ineligible steps in the claims are part of the data gathering process and are not a practical application of the recited judicial exceptions.
The response argues that the claims recite an inventive concept sufficient to satisfy step 2B. It is stated that “one inventive concept of the claims lies in the ordered combination of steps centered on using lymphatic channel fluid and analysis relative to lymph node material to diagnose and stage cancer in ways not achievable with conventional blood-based liquid biopsy.”
These arguments are also not persuasive because the broadly recited collecting a fluid sample and detecting an indicia of cancer in the fluid were well-known, routine and conventional in the prior art. It is noted that the claims do not also require performing active steps of obtaining a lymph node sample and detecting the indicia of cancer in the lymph node sample and do not require that this is performed in any particular order. Further, the diagnosing, to the extent that it is recited in the preamble, is not a patent-eligible step that can be relied upon as adding something significantly more to the recited judicial exception since it is itself a judicial exception of an abstract idea / process.
New 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 17 and 19 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 17 is indefinite over the recitation of “is detected at a lower level in the lymph node.” metastases.” It is unclear as to how this recitation relates back to the remainder of the claim because the claim does not recite a step of detecting the indicia of cancer in a lymph node. It is thereby unclear as to whether the claim is intended to require a step of detecting the indicia in the lymph node and detecting a lower level than in the lymphatic fluid or if the claim encompasses methods wherein it is merely a property of the amounts of the indicia that it is necessarily present at a lower level in the lymph node than in the lymphatic fluid.
Claim 19 is indefinite over the recitation of “collected fluid over time.” The general recitation of “fluid” makes the claim unclear as to whether the fluid is the lymphatic fluid (i.e., “the fluid”) or another unspecified fluid.
New Claim Rejections - 35 USC § 112- New Matter
6. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 19 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The disclosure as originally filed does not provide basis for the recitation in new claim 19 of “wherein assessing disease progression comprises determining spread of indicia along sequential lymphatic channels.”
In the amendment filed on 28 May 2026, Applicant states “Support for the amendments can be found at paragraphs [0009], [0012], [0014-0015], [0018], [0022], and [0039-0040].”
However, the cited portions of the specification, with respect to the published application, do not disclose detection of the indicia of cancer in sequential lymphatic channels, particular to assess the progression of cancer.
If Applicant maintains that the originally filed disclosure provides basis for the amended claims, Applicant should point to specific teachings (e.g., by paragraph number) in the present application to establish basis for each of the recitations set forth in the claims. Particularly, since there is no literal basis in the original disclosure for “sequential lymphatic channels,” Applicant should explain how the cited teachings provide basis for the above cited limitation in new claim 19.
See MPEP 2163 II at “(b) New Claims, Amended Claims, or Claims Asserting Entitlement to the Benefit of an Earlier Priority Date or Filing Date under 35 U.S.C. 119, 120, 365, or 386” which states:
“To comply with the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, or to be entitled to an earlier priority date or filing date under 35 U.S.C. 119, 120, 365, or 386, each claim limitation must be expressly, implicitly, or inherently supported in the originally filed disclosure.”
Modified Claim Rejections - 35 USC § 103
7. 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.
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) 1-3, 5, 7, 10-11, 13, 15, 17-18 and 20-22 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).
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).
Nowecki does not recite a step of comparing (assessing) the amount of the melanoma marker nucleic acids from the lymphatic fluid 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 to the 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 of Nowecki so as to have compared the amount of the melanoma marker nucleic acids in the lymphatic fluid to the amount present in a lymph node sample. One would have been motivated to have made such a comparison in order to have determined if the results obtained with the lymphatic drainage fluid were accurate for the prediction of metastasis.
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 claims 3, 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”).
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 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 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.
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.
Regarding claim 17, Nowecki does not teach that the amount of the melanoma markers in the lymphatic fluid is less than the amount in the lymph node. 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 detected higher levels of the melanoma markers in the lymphatic fluid as compared to the lymph node in those instances in which there was a minimal degree of metastasis of the melanoma.
Regarding claim 18, the method of Nowecki of detecting the melanoma marker nucleic acid in the lymphatic fluid does not require isolating tumor cells.
Regarding claims 20 and 21, these claims recite inherent properties of the relative amounts and do not distinguish the claimed method over that of Nowecki.
Regarding claim 22, modification of the method of Nowecki as set forth above necessarily requires measuring the amount of the melanoma marker nucleic acids (indica of cancer) in the lymphatic fluid and in a lymph node sample.9. Claim(s) 9 and 16 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) 19 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 Ryu, B. (U.S. 20120201750).
The teachings of Nowecki are presented above.
Nowecki does not specifically teach that assessing disease progression comprises detecting an increase in the level of the melanoma marker nucleic acids collected over time. However, Nowecki teaches that “(t)he status of regional lymph nodes is a powerful prognostic factor for the outcome of cutaneous melanoma” (p. 603, col. 1 final para). Nowecki also teaches that lymphatic fluid is assayed for the melanoma marker nucleic acids as indicative of metastasis and melanoma progression (e.g., “Discussion at p. 603, col. 1 final para to col. 2, second para and p. 604, col. 1 final para).
Further, Rhu teaches methods of assaying biological samples from a subject, including lymphatic fluid samples, for markers of melanoma metastasis (e.g., para [0017-0018], [0037] and [0075]). Rhu also teaches obtaining samples from the subject at different time points and assaying the samples for the melanoma markers as indicative of the melanoma status of the subject (e.g., para [0123-0124]). Rhu also teaches that samples can be collected before, during and after treatment to evaluate the effectiveness of the treatment (e.g., para [0083]).
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 of Nowecki so as to have collected multiple lymphatic fluid samples from a subject and to assayed the samples for the level of the melanoma marker nucleic acids over time, as taught by Ryu. One would have been motivated to have done so in order to have provided additional information regarding the progression of the melanoma over time and/or to monitor the effectiveness of treatment for the melanoma.
Response to Remarks:
The response argues:
“independent claim 1 recites assessing relative amounts of indicia of cancer in lymphatic channel fluid and a lymph node. Nowecki neither teaches nor enables this limitation. In Nowecki, lymph nodes are excised before lymphatic fluid is collected, such that its methodology structurally precludes any contemporaneous assessment of indicia between lymphatic channel fluid and lymph node material. A reference that renders the claimed assessment impossible by design cannot disclose the elements of amended claim 1 arranged as required, and therefore cannot serve as a proper primary reference for an obviousness rejection.
Thus, Nowecki does not merely omit a limitation, but fails to disclose a method in which indicia are obtained from both lymphatic channel fluid and a lymph node within a common diagnostic framework, as required by claim 1..”
These arguments have been fully considered but are not persuasive. First, the rejection is made under 35 U.S.C. 103 and not under 35 U.S.C. 102. Thereby, there is no requirement for Nowecki to teach the claimed invention. Rather, the rejections is based on the finding that the teachings of Nowecki when considered as a whole would have suggested the claimed method and enabled the claimed method.
Secondly, the fact that lymph nodes are excised before lymphatic fluid is collected in the method of Nowecki does not preclude assessing the level of the indicia in the lymphatic fluid and in the lymph node. There is no requirement in the claims that the samples are obtained at the same time, as Applicant appears to be arguing. The claims do not even require obtaining the lymph node sample and detecting the indicia of cancer in the lymph node sample. The claims encompass methods wherein the lymph node sample may have been obtained and previously assayed for the indicia of cancer or stored and subsequently analyzed for the indicia of cancer.
Modified Rejections - Double Patenting
12. 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 1-3, 7, 9-11 and 13-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-23, 29, 30 and 32-37 of copending Application No. 17/947,861 (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 ‘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. Note that the specification of ‘861 defines a drain fluid as including a lymphatic fluid (e.g., para [0007]) and claim 23 of ‘861 recites separating lymphatic fluid from the surgical drain fluid The claims of ‘861 (e.g., claim 15 and 29) also encompass detecting and comparing the amount of the cancer biomarkers, including nucleic acid biomarkers (claim 19), in the surgical drain fluid / lymphatic fluid to the amount of the cancer biomarkers in lymph nodes. Accordingly, when considered as a whole, the claims of ‘861 suggest the presently clamed methods of the claims of ‘861 suggest the claimed methods of collecting fluid from a lymphatic channel of a patient suspected of having cancer; detecting a biomarker / indicia of cancer; and assessing relative amounts of a biomarker / indicia of cancer in a lymphatic channel fluid sample relative to that in a lymph node.
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 present claim 9, the claims of ‘861 include detecting the biomarker in a blood sample (e.g., claim 17 and 29).
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, 15 and 19, 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 18 and 34). 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.
Regarding present claim 17, the claims of ‘861 do not recite that the amount of the biomarker in the lymphatic fluid is less than the amount in the lymph node. 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 detected higher levels of the cancer biomarker in the lymphatic fluid as compared to the lymph node in those instances in which there was a minimal degree of metastasis of the cancer.
Regarding claim 18, the methods of ‘861 do not require isolating tumor cells to detect the biomarker in the lymphatic fluid.
Regarding claims 20 and 21, these claims recite inherent properties of the relative amounts and do not distinguish the claimed method over the method claimed in ‘861.
Regarding claim 22, the method claimed in ‘861 encompasses measuring the amount of the biomarker (indicia of cancer) in the lymphatic fluid and in a lymph node sample (e.g., claims 15, 21 and 29).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.New Claim Rejection:
13. Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-23, 29, 30 and 32-37 of copending Application No. 17/947,861 (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 ‘861 are discussed above.
The claims of ‘861 as amended do not recite that the lymphatic 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 ‘861 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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Remarks:
The response states that the amended claims are not obvious over the claims of ‘861 because the claims of ‘861 do not require “assessing relative amounts of indicia based on measurements in lymphatic channel fluid and in a lymph node.”
This argument has been fully considered but is not persuasive. Claim 15 of ‘861 recites “evaluating the likelihood of metastatic disease based on the presence of the biomarker in both the drain fluid and the lymph node” and claim 21, which depends from claim 15 recites, “further comprising comparing an amount of the biomarker in the drain fluid a to an amount determined in the lymph node.” The specification of ‘861 defines the drain fluid as encompassing lymphatic fluid. Also claim 22 of ‘861 recites separating lymphatic fluid from the drain fluid. Claim 29 of ‘861 recites “measuring a biomarker in surgical drain fluid and at least one of lymph node tissue; or blood; and assessing metastatic disease based on relative amounts of said biomarker.” Accordingly, the claims of ‘861 suggest the claimed method, including the step of assessing relative amounts of a biomarker / indicia of cancer in a lymphatic channel fluid sample relative to that in a lymph node.
The response requests that the rejection be held in abeyance since the rejection is provisional.
However, rejections are not held in abeyance. The rejection is maintained for the reasons set forth above.
Conclusion
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.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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