DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Amendments
Applicant has amended claims 15, 22, and 29 to replace “measuring” and “lymphatic fluid” with “identifying” and “surgical drain fluid”, respectively. Claims 16-18, 21 and 23 have also been amended to maintain consistency with said independent claims, while claim 24 has been canceled.
Election/Restrictions
Claims 1-14, 25-28, and 31 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 15-23 and 29-30 have been considered on the merits.
Information Disclosure Statement
The two information disclosure statements (IDSs) submitted on 11/20/2025 are in compliance with the provisions of 37 C.F.R. 1.97. All references cited in the IDSs have been fully considered.
Specification
RE: Objection to the specification
The substitute abstract no longer exceeds the maximum allowed number of words or lines of text. Thus, the objection to the specification has been withdrawn.
Claim Objections
RE: Objection to the claims
All minor informalities in claim 22 have been corrected. The objection to said claim has therefore been withdrawn.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
RE: Rejection of claims 15-24 and 29-30 under 35 U.S.C. 101
Applicant points out that that claims have been amended to use “a surgical drain fluid” instead of “lymphatic fluid”, as well as perform the steps of “measuring” and “detecting” a biomarker instead of “identifying” and “determining” it. Given that these amendments require laboratory instruments/reagents, transformation of matter, and analysis of results, it is argued that the claimed laboratory assays are no longer drawn to a natural phenomenon and abstract idea. Even if the claims are considered to recite a judicial exception, applicant asserts that measuring a biomarker in a surgical drain fluid is practical and therefore integrates the alleged judicial exception into a practical application. Applicant further contends that analysis of a surgical drain fluid is not well-understood, routine, or conventional.
All arguments have been fully considered but are found unpersuasive. The claimed methods are based on the relationship between the presence of a biomarker in both a surgical drain fluid and a lymph node (or blood), or the relative amounts of circulating tumor cells and cell-free DNA in a surgical drain fluid, with the probability of having metastatic disease. Since this relationship is a naturally occurring correlation, the claims recite a law of nature. In addition, evaluating the likelihood or assessing the risk of metastatic disease, as well as comparing the ratio of circulating tumor cells to cell-free DNA at two or more time points (which is a mathematical calculation), are processes that can be performed in the human mind. It is therefore respectfully submitted that the claims are still considered to recite a law of nature and an abstract idea.
Furthermore, although measuring a biomarker entails laboratory assays, this step does not involve the use of a specific machine and is not applied to effectuate a particular treatment for a disease. The claims recite the measuring step at a high level of generality such that they do not impose meaningful limits on the recited law of nature. Thus, the recited judicial exceptions are not integrated into a practical application.
Lastly, the claimed methods are well-known and routine in the field of cancer diagnosis. Various references, including the cited prior art Chin et al. (US 2011/0182881 A1) and Han et al. (Cancers 2020, Vol. 12, 2866, pages 1-18), indicate that measuring a biomarker in a biological sample such as body fluids and tissues obtained from a subject are used to diagnose metastatic disease. This is supported, for example, by Broggi et al.’s findings (Journal of Experimental Medicine 2019, Vol. 216, pages 1091-1107) that lymphatic exudate (a type of surgical drain fluid) is enriched with tumor-associated factors and extracellular vesicles containing melanoma-associated proteins and miRNAs, which can be utilized to diagnose early or late metastasis.
The Office thus maintains the rejections under 35 U.S.C. 101. But in consideration of claim amendments, the rejections of record have been modified.
Modified rejections
Claims 15-23 and 29-30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature and an abstract idea without significantly more.
The United States Patent and Trademark Office (USPTO) issued a revised guidance for evaluating subject matter eligibility, referred to as “2019 Revised Patent Subject Matter Eligibility Guidance”, which became effective on January 7, 2019 (see 84 Fed. Reg. 50) and updated on October 2019 and July 2024. In the instant application, claims 15-23 and 29-30 recite a law of nature and an abstract idea. These judicial exceptions are not integrated into a practical application, and the claims do not include additional elements that are sufficient to amount to significantly more than said judicial exceptions as explained below:
Subject Matter Eligibility Guidance
A three-step inquiry has been established to determine subject matter eligibility under 35 U.S.C. 101, in accordance with MPEP 2106:
Step (1). Is the claim directed to a process, machine, manufacture, or composition of matter?
Step (2A). Is the claim directed to a law of nature, natural phenomenon (product of nature), or an abstract idea?
Prong 1 – Does the claim recite a law of nature, natural phenomenon, or an abstract idea?
Prong 2 – If the claim recites a judicial exception, does it recite additional elements that integrate the judicial exception into a practical application? Limitations that are indicative of integration into a practical application include:
Improvements to the functioning of a computer, or to any other technology or technical field. See MPEP 2106.05(a)
Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. See Vanda Memo
Applying the judicial exception with, or by use of, a particular machine. See MPEP 2106.05(b)
Effecting a transformation or reduction of a particular article to a different state or thing. See MPEP 2106.05(c)
Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception. See MPEP 2106.05(e) and Vanda Memo.
Step (2B). If the recited judicial exception is not integrated into a practical application, does the claim recite additional elements that amount to significantly different than the judicial exception such that they provide an inventive concept? This step includes evaluation of the same considerations under Step (2A), Prong 2, as well as two additional considerations:
Adding a specific limitation or combination of limitations that are not well-understood, routine, conventional activity in the field, which is indicative that an inventive concept may be present; and
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, which is indicative that an inventive concept may not be present.
Analysis in View of the Interim Guidance
The answer to Step (1) is “yes” since the claims are directed to methods, which are a statutory category.
The answer to Step (2A) is “yes” because the claimed methods are directed to a law of nature and abstract idea.
Prong 1: The claimed methods entail predicting metastatic disease based on the presence of a biomarker in both a surgical drain fluid and lymph node (claims 15-21), assessing cancer metastasis based on the changing ratio of circulating tumor cells (CTCs) to cell-free tumor DNA (cftDNA) over two or more time points (claims 22-23), or assessing metastatic disease based on the relative amounts of a biomarker in surgical drain fluid and lymph node tissue, or in blood (claims 29-30). These methods correlate the presence or relative abundance of a biomarker with the likelihood or risk of metastasis or cancer metastasis (i.e., a natural relationship between the presence or relative abundance of a biomarker, such as CTCs and cftDNA, and metastatic disease or cancer metastasis) and therefore recite a law of nature.
Moreover, the steps of “evaluating the likelihood of metastatic disease” or “assessing risk of metastasis”, as well as “comparing” the ratio of CTCs to cftDNA at two or more time points (claim 22) or the amount of the biomarker in the surgical drain fluid to the amount determined in the lymph node (as further required in claim 21) are not meaningfully different from the concepts that the Courts have identified as abstract idea. See PerkinElmer, Inc. v. Intema Ltd. (96 Fed. Appx. 65, 105 U.S.P.Q.2d 1960 (Fed. Cir. 2012)). They are considered mental steps in which collected information is evaluated or analyzed in the human mind. Thus, under Prong 1 of Step 2A, the claims recite law of nature and abstract idea.
Prong 2: There are no additional elements that integrate the recited judicial exception into a practical application. The recited judicial exceptions are not applied with, or use of, a particular machine, nor are they applied to effect a particular disease or medical condition (i.e., no step of administering a particular treatment).
The answer to Step (2B) is “no”. Claims do not recite additional elements that amount to significantly different than the judicial exceptions. Determining the likelihood or risk of metastatic disease based on the presence or relative amount of a biomarker in a biological sample like a body fluid is well-understood and conventional in the art. For example, Chin et al. (US 2011/0182881 A1) discloses biological signatures and genetic “determinants” associated with cancer metastasis (i.e., metastasis biomarkers), as well as methods of using them (par. [0002]). In one aspect, the method of use aims to diagnose a metastatic tumor or assess the risk of metastasis by measuring determinants in a subject’s sample and comparing the measured amounts to reference values (par. [0097]-[0099]), wherein the sample can be biological samples isolated from a subject including tissues and body fluids such as blood, serum, and lymphatic fluid (par. [0065]). Although Chin et al. does not list surgical drain fluid, a person with ordinary skill in the art would have recognized that it would be an applicable body fluid given that a surgical drain fluid is known to comprise blood, serum, and lymphatic fluid. Broggi et al. (Journal of Experimental Medicine 2019, Vol. 216, pages 1091-1107) demonstrates that lymphatic exudate, which is a type of surgical drain fluid, is enriched with tumor-associated factors and extracellular vesicles containing melanoma-associated proteins and miRNAs that can be utilized to diagnose metastasis (Abstract, page 1091). Similarly, Greenberg et al. (The Israel Medical Association Journal 2003, Vol. 5, pages 649-652) detected the biomarker MUC-1 in axillary drainage collected from patients with breast cancer on postoperative day 2, and found a correlation between MUC-1 presence and the number of metastatic lymph nodes. Broggi et al. and Greenberg et al.’s teachings indicate that a surgical drain fluid is a body fluid that serves as a source of biomarkers and is thus a suitable sample for evaluating the risk of metastasis. Furthermore, Han et al. (Cancers 2020, Vol. 12, 2866, pages 1-18) shows in vivo detection of lymphatic circulating tumor cells using photoacoustic and fluorescent flow cytometry, wherein said lymphatic CTCs serve as prognostic markers of metastasis (Abstract, page 1).
Claims 15-23 and 29-30 as a whole therefore do not qualify as eligible subject matter.
Claim Interpretation
Claims have been amended to require measuring a biomarker such as circulating tumor cells and cell-free DNA in a surgical drain fluid. The term “surgical drain fluid” is interpreted to refer to “a fluid that flows out passively, or is actively drained, from a surgical wound site during and/or after surgery”.
In claim 29, the first step recites “measuring a biomarker in surgical drain fluid and lymph node tissue, or blood”. The presence of a comma before the conjunction “or” is interpreted to mean the biomarker can be measured in either: (i) surgical drain fluid and lymph node tissue; or (ii) blood.
Claim Rejections - 35 USC § 103
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.
RE: Rejection of claims 15-19 and 29 under 35 U.S.C. 103 over Nordgard
Traversal of rejections is based on Nordgard only disclosing analysis of lymph tissue and blood, and that this deficiency is not cured by Dawson et al., Gupta et al., Rossi et al., and Yen et al. as these secondary references only teach analyzing serum, plasma, and/or blood.
Applicant’s traversal has been fully considered and is found partly persuasive. It is conceded that none of the cited prior art teaches measuring a biomarker in a surgical drain fluid as now required by the claims.
However, it should be noted that claim 29 is open to measuring a biomarker in blood (i.e., as an alternative to measuring a biomarker in both surgical drain fluid and lymph node tissue). The rejections on claims 29-30 are therefore maintained. The rejections on the other claims have therefore been withdrawn.
Maintained rejections
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Nordgard (WO 2013/164787 A1).
Nordgard discloses methods for detection and/or diagnosis of cancer in a biological sample obtained from a subject such as a lymph tissue sample or a blood sample (Abstract). To achieve this, proline/histidine/glycine-rich 1 (PHGR1) nucleic acid and polypeptides, and fragments thereof, are utilized as cancer biomarkers. Their presence in a biological sample obtained from a subject is indicative of the presence of a cancer in said subject (lines 1-9, page 2).
One aspect of the disclosed methods is a method monitoring the metastasis of a cancer in a subject. The method comprises: (a) measuring the level of PHGR1 polypeptide or PHGR1 mRNA in first and second biological samples which have been obtained from the subject at first and second time points; and (b) comparing the levels of PHGR1 polypeptide or PHGR1 mRNA in the first and second biological samples (lines 18, page 3). An increase in the level of PHGR1 polypeptide or PHGR1 mRNA in the sample taken at the later time point compared to the corresponding level of PHGR1 polypeptide or PHGR1 mRNA in the sample taken at the earlier time point is indicative of an increase in the number of circulating cancer cells in the patient, while a decrease in the level of PHGR1 polypeptide or PHGR1 mRNA in the sample taken at the later time point compared the corresponding level of PHGR1 polypeptide or PHGR1 mRNA in the sample taken at the earlier time point is indicative of a decrease in the number of circulating cancer cells in the patient (lines 9-16, page 3).
The biological sample can be any body fluid or tissue such as from lymph nodes, lymph fluid, and blood (lines 14-29, page 6).
Nordgard is comparable to the instant application for the following reasons:
Regarding claim 29: detecting PHGR1 polypeptide or mRNA (i.e., PHGR1 protein or nucleic acid serves as a biomarker) in a biological sample like blood is analogous to the step “measuring a biomarker in surgical drain fluid and lymph node tissue, or blood”.
A person with ordinary skill in the art before the effective filing date of the claimed invention would have known that an observation of increased PHGR1 polypeptide or mRNA level in the tested biological samples such as lymph nodes over a time period indicates metastasis, which is analogous to the step “assessing metastatic disease based on relative amounts of said biomarker”.
Claims 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Nordgard (WO 2013/164787 A1) in view of Yen et al. (WO 2021/183821 A1).
Nordgard’s teachings are set forth above and applied herein. Nordgard is found to render claim 29 obvious.
The disclosed method is comparable to the following claim:
Regarding claim 30: Nordgard differs from the instant claim in that it does not teach the amount of the biomarker being “weighted”.
Yen et al. discloses methods for differentiating nucleic acids originating from tumor and non-tumor origin (Abstract). In some embodiments, values of performance metrics include weighted precision, which involves calculating metrics for each label and finding their average weighted by support in order to determine the number of true instances for each label (par. [0094]). Given that biomarkers have different degrees of relevance to an aspect of a disease, weighting their amount would have been obvious as it assigns the relative importance or weight of each biomarker. In addition, biomarker levels can fluctuate due to variability in biological samples and testing procedures. It can be expected that weighting the biomarker amounts would give the benefit of adjusting for such variations and help improve prediction of metastatic disease.
Thus, claim 30 is obvious over Nordgard in view of Yen et al..
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
RE: Nonstatutory double patenting
Applicant traverses the rejections based on the amended claims being no longer obvious over the claims of co-pending application 17/947871.
The traversal has been fully considered and is found not persuasive. The amendments now require measuring a biomarker in a surgical drain fluid, which is not taught by the co-pending application. However, this new limitation is obvious in light of the teachings of newly found prior art.
New rejections
Claims 15-21 and 29-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of co-pending Application No. 17/947871 in view of Broggi et al. (Journal of Experimental Medicine 2019, Vol. 216, pages 1091-1107) and Greenberg et al. (The Israel Medical Association Journal 2003, Vol. 5, pages 649-652).
The co-pending application is drawn to a method for disease diagnosis comprising collecting fluid from a lymphatic channel of a patient suspected of having cancer and identifying indicia of cancer in said fluid. The indicia of cancer include one or more of a nucleic acid, a protein, a tumor cell, as well as a ratio of circulating tumor cells to cell-free DNA. In some embodiments, the method further comprises identifying indicia of in-transit metastases, or assessing relative amounts of said indicia in said lymphatic channel as compared to a lymph node. In another embodiment, the method additionally comprises determining amounts of said indicia and comparing said amounts to amounts identified in blood.
The claims of the co-pending application are different from the instant claims in that a surgical drain fluid is not used for detecting an indicia of metastasis (i.e., a biomarker).
Despite this, Broggi et al. demonstrates that lymphatic exudate, which is a type of surgical drain fluid, is enriched with tumor-associated factors and extracellular vesicles containing melanoma-associated proteins and miRNAs that can be utilized to diagnose metastasis (Abstract, page 1091). Greenberg et al. also detected biomarkers like MUC-1 in axillary drainage collected from patients with breast cancer, and found a correlation between MUC-1 presence and the number of metastatic lymph nodes. The teachings of Broggi et al. and Greenberg et al. indicate that a surgical drain fluid is a suitable sample for determining the risk of metastasis. Accordingly, a person with ordinary skill in the art before the effective filing date of the claimed invention would have modified the co-pending application’s method by measuring an indicia of metastasis in a surgical drain fluid. There is reasonable expectation of success since a surgical drain fluid is a rich source of biomarkers.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHELLE F PAGUIO FRISING whose telephone number is (571)272-6224. The examiner can normally be reached Monday-Friday, 8:00 a.m. - 4:00 p.m..
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, Melenie L. Gordon can be reached at (571) 272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Michelle F. Paguio Frising/Primary Examiner, Art Unit 1651