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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on 6/18/2026 has been entered.
Claim Amendments
Applicants have amended claim 17 to replace “identifying” with “measuring”, claim 21 to delete “and comparing said amount”, claim 22 to replace “cell-free DNA to circulating tumor cells” with “circulating tumor cells to cell-free DNA”, and claim 23 to add the limitation “wherein the circulating tumor cells and cell-free DNA are measured in the separated lymphatic fluid”. Moreover, claim 29 has been amended to clarify that a biomarker is measured not only in surgical drain fluid but also in “at least one of” lymph node tissue or blood. Claims 1-14, 25-28, and 31 have been canceled, while claims 32-37 have been added.
Election/Restrictions
With cancelation of claims 1-14, 25-28, and 31 which are directed to non-elected groups of invention, only the claims belonging to Invention III remain. Accordingly, claims 15-23, 29-30, and 32-37 have been examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 6/18/2026 is in compliance with the provisions of 37 C.F.R. 1.97 and has been fully considered.
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 15-23 and 29-30 under 35 U.S.C. 101
Rejections are traversed because the claimed methods are allegedly not directed to a law of nature nor an abstract idea. Applicants assert that the office action improperly dissects the claims into individual limitations by evaluating them in isolation rather than the claims a whole. The first step of measuring a biomarker requires the use of laboratory instruments and reagents, transformation of matter, and analysis of results. Moreover, the subsequent step(s) require physical collection and laboratory analysis of particular sample types. Thus, the claimed invention is allegedly directed to laboratory assays and interpretations thereof, which cannot be mistaken for a natural phenomenon nor a mental process. And even if the claims do recite a judicial exception, applicants argue that the claims integrate the judicial exception into a practical application because there is (i) transformation of the surgical drain fluid from a raw biological sample into analyzed data and (ii) application of the judicial exception to a particular technological environment as a specific sample type is analyzed. Applicants also contend that new claims 32 and 36 recite administering a treatment based on the evaluation or assessment of metastatic disease.
All arguments have been fully considered but are found unpersuasive. First, it should be noted that Step 2A of USPTO’s Subject Matter Eligibility Guidance (SME) consists of a two-prong inquiry, wherein Prong 1 determines whether claims recite a law of nature, natural phenomenon, or an abstract idea. In this case, claims have been considered to recite a law of nature and an abstract idea based not only on the first step but also on the other steps. Claims 15 entails initially measuring a biomarker in a surgical drain fluid and then detecting whether said biomarker is present in a lymph node before evaluating the likelihood of metastatic disease based on the presence of the biomarker in both the drain fluid and the lymph node. Similarly, claim 29 involves measuring a biomarker in surgical drain fluid and at least one of lymph node tissue or blood prior to assessing metastatic disease based on relative amounts of said biomarker. On the other hand, claim 22 comprises first measuring circulating tumor cells and cell-free DNA in surgical drain fluid at two or more time points, followed by comparing their ratio at said two or more time points, and finally assessing risk of metastasis as a changing ratio of circulating tumor cells to cell-free DNA over said two or more time points. These methods depend on the relationship between the presence of a biomarker in both a surgical drain fluid and a lymph node (and/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 based on all the steps. As set forth in the last office action, this relationship is a naturally occurring correlation. Evaluating the likelihood of metastatic disease or assessing metastasis, and comparing ratios, are also considered mental processes. Thus contrary to applicants’ assertion, the claimed methods have been determined to recite a law of nature and an abstract idea based on the claims as a whole.
With regards to applicants’ argument that the judicial exception is integrated into a practical application, it is respectfully submitted that deriving analyzed data from a raw biological specimen, or separating lymphatic fluid from drain fluid, is not considered a transformation of a particular article to a different state or thing. Under MPEP § 2106.05(c), the transformation must be particular and extensive/significant such that it imposes meaningful limits such as creation of new products or change in the article’s chemical property/function. The nature of the article must also be factored in since a physical or tangible object is more likely to provide significantly more than an intangible concept. For example, converting fat and water in the presence of heat into fatty acids and glycerol is a specific and substantial process that can be considered a transformation into a different state or thing. Another example is generating precision-molded synthetic rubber products from raw, uncured rubber. In contrast, measuring or detecting a biomarker in a surgical drain fluid aside from lymph node and/or blood does not qualify as a transformation (i.e., the biological samples remain unchanged), nor separating lymphatic fluid from the surgical drain fluid (removing other components is a physical change that does not significantly alter the nature of the surgical drain fluid). Furthermore, using a certain sample type does not necessarily mean that the recited judicial exception is applied to a particular technology especially since none of the claims specify how a biomarker is measured or detected.
With regards to the additional step specified in the new claims, the “treatment” is recited at a high level of generality. Given that the administration step is not particular and merely instructs to apply the exception in a generic way, the administration step does not integrate the mental analysis step into a practical application.
The instant claims are thus maintained as subject matter ineligible. However, the rejections of record have been modified to address amendments including the addition of new claims.
Modified rejections
Claims 15-23, 29-30, and 32-37 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. Although new claims further entail administering a treatment based on the evaluation or assessment results, it is generic as the treatment type and administration regimen (dosage, frequency, duration) are not specified.
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”.
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 claim 29 over Nordgard; and claims 29-30 over Nordgard in view of Yen et al.
Claim 29 has been amended to require measuring a biomarker in a surgical drain fluid as well as lymph node tissue and/or blood. Applicant points out that this requirement is not taught by Nordgard and that Yen et al. does not cure Nordgard’s deficiency.
All arguments have been fully considered and are found persuasive. None of the cited prior art specifically teaches measuring a biomarker in a surgical drain fluid in addition to measuring it in a lymph node tissue, blood, or both. Hence, the prior art rejections have been withdrawn.
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 argues that the claims of co-pending application 17/947871 do not relate to use of surgical drain fluid and that the double patenting rejections no longer apply due to all claim amendments in the instant application and co-pending application.
The arguments been fully considered and are found not persuasive. As discussed in the last office action, the co-pending application does not use surgical drain fluid for predicting metastatic disease or assessing cancer metastasis/metastatic diseases, but this requirement is found obvious over the cited prior art. It is also respectfully submitted that none of the amendments to the claims allows withdrawal of the double patenting rejections. Moreover, a new dependent claim of co-pending application 17/947871 recites that the relative amounts of cancer indicia indicate whether cancer is localized, lymphatically spreading, or metastatic. The rejections of record are thus proper but have been modified to account for claim amendments.
Moreover, an updated inventor search revealed a new co-pending application which necessitates new grounds of rejection and are set forth below.
Modified rejections
Claims 15-21 and 29-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, and 7-22 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 cancer diagnosis comprising collecting fluid from a lymphatic channel of a patient suspected of having cancer, detecting indicia of cancer in said fluid, and assessing relative amounts of said indicia in said fluid and in a lymph node. 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 an embodiment, the relative amounts indicate whether cancer is localized, lymphatically spreading, or metastatic.
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.
New rejections
Claims 15-21, 29-30, 32-33, and 36-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, 34-39 of co-pending Application No. 18/838078 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 directed to a method for detecting an exosome-associated biomarker in a biological sample by isolating extracellular vesicles from a surgical drain fluid and detecting at least one biomarker produced in the extracellular vesicles. The biomarker can be one or more of a protein, nucleic acid, saccharide molecule, glycosylated protein, lipid molecule, and may exist in monomeric, oligomeric and/or multimeric form.
Although the claims at issue are not identical, they are not patentably distinct from each other because an embodiment of the co-pending application specifies that the presence, or absence, or differential expression of the biomarkers relative to a healthy control is an indication of disease including cancer like metastatic cancer. In addition, the co-pending application entails administering a treatment to the subject before and after quantifying an exosome-associated biomarker from a subject.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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
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