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 .
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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/11/2026 has been entered.
Priority
The present application filed 01/13/2022, is a utility “bypass” application type 35 USA 111(a). Specifically, this application is a continuation of PCT/EP2020/070429, filed 07/20/2020, which claims foreign priority to EP19187478.3, filed on 07/22/2019.
Status of the Claims
Claims 1, 18-20, 24 and 27-40 are pending; claims 18-20 are amended; claims 2-17, 21-23 and 25-26 are canceled; claims 1, 18-20, 24 and 27-40 are examined below.
Maintained Rejections
Claim Rejections - 35 USC § 112
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.
Claims 18-20, 24 and 27-40 are 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 written description rejection.
Claims 18-20 require a first monoclonal antibody and a second monoclonal antibody, wherein the first and second monoclonal antibodies each specifically bind to S100A9 at different and non-overlapping epitopes. Claims 24 and 27-40 require two or more antibodies that specifically bind to S100A9. Claim 27 requires “wherein the two or more antibodies are monoclonal antibodies”.
The specification does not describe which amino acid residues, nucleic acid residues, or other molecular components are present in the genus of agents encompassed by claims 18-20, 24 and 27-40. The specification fails to disclose the structures common to all members of the genus and fails to provide sufficient specific examples of agents to be used. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described. Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement.
Regarding the claimed scope that includes antibodies, the Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies of the claims.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
The specification only discloses one example of specific monoclonal antibodies that specifically bind S100A9 (“S100A9/MR14 ELISA kit from CircuLex/MBL” page 34 line 13). However, only one example of antibodies that specifically bind S100A9 is not considered sufficient evidence to show possession of the genus of monoclonal antibodies encompassed by the claims. Also, after a search in the patent and non-patent literature, there appears to be no other publicly available monoclonal antibodies specific for S100A9 in the market before the effective filing date of the claimed invention. Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the full genus of agents/antibodies encompassed by the claims. Further, given the well-known high level of polymorphism of immunoglobulins and antibodies, the skilled artisan would not have recognized that applicant was in possession of the vast repertoire of encompassed antibodies.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of the genus of claimed antibodies. Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Therefore, claims 18-20, 24-25 and 27-40 do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
New Rejection
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.
Claim 1 is 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 1 recites “A non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising measuring the amount or concentration of S100 calcium-binding protein A9 (S100A9) in a sample of the patient, comparing the measured amount or concentration to a reference, and determining that the patient has dysmenorrhea according to a Visual Analog Scale (VAS) scale and/or lower abdominal pain according to a VAS scale…”.
However, it is not clear how the step of “determining that the patient has dysmenorrhea according to a Visual Analog Scale (VAS) scale and/or lower abdominal pain according to a VAS scale” relates to endometriosis. There appears to be a disconnect between the step of “determining that the patient has dysmenorrhea according to a Visual Analog Scale (VAS) scale and/or lower abdominal pain according to a VAS scale” and the non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis. Because of this, a person having ordinary skill in the art would not recognize the metes and bounds of the claim.
New Rejection
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 35 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 35 recites "[t]he kit of claim 24, wherein the patient is a human female". However, limiting the patient to be a human female does not further limit the kit comprising two antibodies. Therefore, claim 35 fails to further limit claim 24.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
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. For instance, the claims in Diehr, 450 U.S. at 178 n. 2, 179 n.5, 191-92, 209 USPQ at 4-5 (1981), clearly stated a mathematical equation in the repetitively calculating step, and the claims in Mayo, 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012), clearly stated laws of nature in the wherein clause, such that the claims "set forth" an identifiable judicial exception. Alternatively, the claims in Alice Corp., 573 U.S. at 218, 110 USPQ2d at 1982, described the concept of intermediated settlement without ever explicitly using the words "intermediated" or "settlement." See MPEP 2106.04 (II)(A)(1).
Claim 1 recites “[a] non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising measuring the amount or concentration of S100 calcium-binding protein A9 (S100A9) in a sample of the patient, comparing the measured amount or concentration to a reference… wherein the sample is body fluid selected from the group consisting of blood, serum and plasma”. Claim 20 recites “[a] non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising measuring the amount or concentration of S100 calcium-binding protein A9 (S100A9) in a sample of the patient… comparing the measured amount or concentration to a reference, and assessing whether the patient has endometriosis or is at risk of developing endometriosis, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma”.
The natural relationship to which the claims are directed (i.e., the relation between S100A9 and endometriosis) is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring amount or concentration of S100A9 in blood, serum or plasma and the presence of endometriosis.
The correlation between the amount or concentration of S100A9 and endometriosis is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility. Similarly, it is a naturally occurring phenomenon that the amount or concentration of S100A9 is elevated to different extents in endometriosis vs. in other diseases.
Additionally, the claims also recite steps of “comparing the measured amount or concentration to a reference”. The claimed steps of assessing whether a patient has endometriosis or is at risk of developing endometriosis by comparing the measured amount or concentration to a reference may also be categorized as abstract ideas, namely mental processes/ concepts performed in the human mind (such as a doctor simply thinking about the measured amount or concentration of S100A9 in relation to a reference value and making an evaluation, judgment, or opinion). The claims, under their broadest reasonable interpretation, cover performance of assessing whether a patient has endometriosis or is at risk of developing endometriosis solely within the human mind, or by a human using pen and paper. Comparing information regarding a sample to a reference (in this case, comparing a numerical level to a reference value) represents abstract ideas.
Similar concepts involving comparing information regarding a sample or test subject to a reference have been held to be an "abstract mental process", as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014) which involved "comparing BRCA sequences and determining the existence of alterations", the collecting and comparing of known information in Classen, the comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC, as well as Mayo.
Claim 1 further recites “wherein endometriosis is stage I endometriosis according to the revised American Society for Reproductive Medicine (rASRM) staging or stage II endometriosis according to rASRM staging”. This limitation merely narrows the disease to which the natural correlation is drawn to. Therefore, this limitation is also drawn to the judicial exception.
Step 2A, Prong 2
The above-discussed steps of “assessing whether a patient has endometriosis or is at risk of developing endometriosis” and “comparing” the S100A9 concentration to a reference are insufficient to integrate the judicial exception(s) into a practical application because steps corresponding to mental activity, which could be performed in a practitioner’s head, are insufficient to constitute a practical application. In this case, detecting disease and comparing numerical values, represent judicial exceptions and not a practical application thereof.
Claim 1 further recites “determining that the patient has dysmenorrhea according to a Visual Analog Scale (VAS) scale and/or lower abdominal pain according to a VAS scale”. This limitation does not integrate the judicial exception into a practical application because it is insignificant presolution activity (data gathering steps) that do not use, rely on or apply the judicial exception such to amount to a practical application thereof.
Claim 20 also recites “incubating the sample of the patient with a first monoclonal antibody bound to a solid phase and a second monoclonal antibody that is detectably labeled, wherein the first and second monoclonal antibodies each specifically bind to S100A9 at different and nonoverlapping epitopes, thereby forming a sandwich complex comprising the first monoclonal antibody, S100A9, and the second monoclonal antibody, and quantifying the sandwich complex thereby quantifying the amount of S100A9 in the sample of the patient”. Such steps of providing a sample and measuring the concentration of S100A9 therein using a first monoclonal antibody bound to a solid phase and second monoclonal antibody that is detectably labeled are insufficient to integrate the judicial exception(s) because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Furthermore, the steps of measuring S100A9 are recited at a high level of generality and are not tied, for example, to any particular antibody, label or solid phase.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The steps of measuring S100A9 are recited at a high level of generality and is not limited, for example, to any specific testing technique, antibody reagent or solid phase device.
Although measurement of S100A9 is performed using a monoclonal antibodies that specifically bind to S100A9, no particular or specific antibody is set forth. Furthermore, the specification indicates that antibody-based methods were known in the art (see page 23 lines 31-32 and page 24 lines 1-2 “The detection of the first anti-S100A9 antibody/S100A9/second anti-S100A9 antibody complex can be performed by any appropriate means. The person skilled in the art is absolutely familiar with such means/methods”). Given that antibody-based measurements were predominant in the clinical assay art and were also in routine use for determination of S100A9, the requirement that S100A9 is measured by antibody binding does not go beyond routine/ conventional activity and fails to impose meaningful limits on the claim scope.
In this case, it was well-understood, routine and conventional to determine the concentration of S100A9 in blood samples by incubating the sample of the patient with a first monoclonal antibody bound to a solid phase and a second monoclonal antibody that is detectably labeled, wherein the first and second monoclonal antibodies each specifically bind to S100A9 at different and nonoverlapping epitopes, thereby forming a sandwich complex comprising the first monoclonal antibody, S100A9, and the second monoclonal antibody. See for example, Shield-Artin et al. Proteomics Clin. Appl. 2012, 6, 170–181, DOI 10.1002/prca.201100008 (“Shield-Artin”) teaches that “S100A9 concentrations in plasma were determined by ELISA. A commercially available Circulex kit (S100A9/MRP14 ELISA kit Cat # CY-8062, MBL International Corp, Woburn, MA, USA) was purchased and run as per the manufacturer’s instructions” (page 173 col. 1 para. 3). Note that the kit taught by Shield-Artin is the same kit disclosed by the specification page 34 lines 12-14. The instant specification page 34 lines 12-25 discloses that the Circulex kit is a sandwich ELISA that uses two monoclonal antibodies, wherein the first monoclonal antibody is bound to a solid phase and the second antibody is detectably labeled (“The concentration of S100A9 in human serum was determined using the Human S100A9/MR14 ELISA kit from CircuLex/MBL (distributed by Biozol Eching, Germany; catalogue number: CY-8062). The kit utilizes the quantitative sandwich ELISA technique…Microtiter plates are pre-coated with a monoclonal antibody specific for human Sl00A9…100 μL of an enzyme-linked monoclonal antibody specific for S 100A9 is added to the wells”). Therefore Shield-Artin teaches incubating the sample of the patient with a first monoclonal antibody bound to a solid phase and a second monoclonal antibody that is detectably labeled, wherein the first and second monoclonal antibodies each specifically bind to S100A9 at different and nonoverlapping epitopes, thereby forming a sandwich complex comprising the first monoclonal antibody, S100A9, and the second monoclonal antibody for quantifying S100A9 in a blood sample when teaching the use of the S100A9 Circulex kit for measuring S100A9 in plasma.
Ilies et al. Clinica Chimica Acta 477 (2018) 127–134, https://doi.org/10.1016/j.cca.2017.12.008 (“Ilies”) teaches that “protein S100A9 w[as] determined using sandwich enzyme-linked immunosorbent assays (ELISA)… S100A9 was determined by using the S100A9/MRP14 ELISA kit (Circulex catalog number CY-8062, sensitivity< 6.55 pg/mL, intra-assay precision CV = 2.2–6.3% and inter-assay precision CV = 5.0–10.8%) following the manufacturer's instructions” (page 129 col. 1 para. 4). Note that the kit taught by Ilies is the same kit disclosed by the specification page 34 lines 12-14. Therefore, Ilies also teaches the measuring step for quantifying S100A9 in a blood sample.
See, also Cluzeau et al. Haematologica. 2017 Oct 5;102(12):2015–2020. doi: 10.3324/haematol.2016.158857 (“Cluzeau”). Cluzeau teaches that “Human S100A9/MRP14 in patients’ serum and supernatants of the HepG2 cell line was quantified using a CircuLex S100A9/MRP14 enzyme-linked immunosorbent assay (ELISA) Kit (MBL, Nagano, Japan)” (page 2016 col. 1 para. 4 and col. 2 para. 1).
Furthermore, see MPEP 2106.05(d), II, regarding activity the courts have generally recognized as techniques considered to be well-known, routine and conventional activity in the life science arts, see specifically detecting a biomarker in a bodily fluid sample is generally considered insignificant pre-solution activity (is similar to 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)).
In view of the above evidence, the claimed steps of determining the concentration of S100A9 using an antibody do not add any feature that is more than well-understood, purely conventional, or routine in the field of diagnostics and biochemical assay methodologies.
Regarding the limitation of determining that the patient has dysmenorrhea according to a Visual Analog Scale (VAS) and/or lower abdominal pain according to a VAS scale, the specification page 10 lines 11-14 suggests that this is well-understood routine and conventional in the art (“[i]n women with endometriosis dysmenorrhea is associated with the highest perception of pain with a mean VAS score of about 6 (Cozzolino et al. Rev Bras Ginecol Obstet. 2019; 41(3): 170-175)”). Also, Taylor (WO 2018044979 A1) (Cited on PTO-892 9/26/2024) teaches “methods useful for the diagnosis, assessment, and characterization of endometriosis in a subject in need thereof” (Abstract). Taylor further teaches assessment of lower abdominal pain according to a VAS scale in women with endometriosis and reports significantly higher pelvic pain levels in women with endometriosis compared to controls (page 61, lines 2-7).
When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed, e.g., the routine and conventional techniques of detecting a protein using an antibody to that protein. See also MPEP 2106.05(g).
There is also evidence of record to indicate that the additional elements, alone or in combination, do not go beyond well-understood, routine and conventional activity in that others had previously measured S100A9 in patients and also assessed whether the patient had endometriosis or was at risk of developing endometriosis. Giudice (US PG Pub No. 20080318237 A1)-Cite No. 1 on IDS (filed on 02/07/2022) at paragraph 136 and Table 6 teaches measuring S100A9 to assess whether the patient had endometriosis and in claim 1 suggests that this involves the use of biological samples. Furthermore, Giudice also teaches that “"[b]iological sample" includes … blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like)” (paragraph 48).
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
Claim Rejections - 35 USC § 103
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Giudice (US PG Pub No. 20080318237 A1)-Cite No. 1 on IDS (filed on 02/07/2022) in view of Taylor (WO 2018044979 A1) (Cited on PTO-892 9/26/2024).
Regarding claim 1, Giudice suggests a non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis (“[t]he present invention provides biomarkers for the diagnosis and prognosis of endometriosis…by detecting the expression levels of biomarkers, which are differentially expressed (up- or down-regulated) in endometrial cells from a patient with endometriosis” Abstract, claim 1), comprising measuring the amount or concentration of S100A9 in a sample of the patient, comparing the measured amount or concentration to a reference (“[t]he list of differentially expressed genes during the mid-secretory phase identified in the current study was compared with the gene list previously obtained in a comparison of endometrial gene expression profiles during the implantation window in women with vs. without minimal/mild endometriosis (Kao L C et al. (2003) Endocrinology 144:2870-81). The two datasets shared five up-regulated genes and twelve down-regulated genes of 1.5 fold or greater (Table 6). Four of the five upregulated genes are involved in the immune (GZMA, C4BPA) or inflammatory (S100A8, S100A9) response” para. 136, claim 1), wherein the sample is body fluid selected from the group consisting of blood, serum and plasma (“"Biological sample" includes…Such samples include blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like” para. 48, “Predictive, Diagnostic, and Prognostic Methods…as measured using a biological sample such as an endometrial biopsy or a sample of a bodily fluid” para. 85, “The term "differentially expressed", "differentially regulated", or "altered expression" refers generally to a protein or nucleic acid that is overexpressed (upregulated) or underexpressed ( downregulated) in one sample compared to at least one other sample, generally in a patient with endometriosis, in comparison to a patient without endometriosis, in the context of the present invention” para. 52), and wherein endometriosis is stage I endometriosis according to the revised American Society for Reproductive Medicine (rASRM) staging or stage II endometriosis according to rASRM staging (paragraph 136, Table 6). Although Giudice does not use the language rASRM staging, Giudice discloses “mild endometriosis” for the S100A9 biomarker, which is stage II endometriosis as per page 5, line 15 of the instant disclosure. Also, although Giudice does not use the language “non-invasive” the teaching of a blood sample for use in the methods of diagnosing endometriosis inherently provides a non-invasive method. Giudice further teaches that “[e]ndometriosis affects 6-10% of women in the general population and 35-50% of women with pain and/or infertility” (para. 4). Giudice further teaches that “[t]he main clinical symptoms of endometriosis are pelvic pain, bleeding and infertility” (para. 5).
Giudice fails to teach wherein the sample is body fluid selected from the group consisting of blood, serum and plasma in a manner consistent with anticipation, i.e. there is some picking and choosing involved in order to arrive at the sample being blood, serum or plasma. Giudice teaches wherein the sample is body fluid selected from the group consisting of blood, serum and plasma from a finite list of possible biological samples to be used in the method of assessing whether a patient has endometriosis or is at risk of developing endometriosis (para. 48). Furthermore, Giudice fails to teach determining that the patient has dysmenorrhea according to a Visual Analog Scale (VAS) scale and/or lower abdominal pain according to a VAS scale.
Taylor teaches “methods useful for the diagnosis, assessment, and characterization of endometriosis in a subject in need thereof” (Abstract).Taylor also teaches that diagnosis of endometriosis relies on invasive procedures like laparoscopy at late stages of the disease, and thus there is a need for non-invasive blood biomarkers of endometriosis for early diagnosis and treatment (“The major symptoms of endometriosis are pelvic pain in 50% of patients (Eskenazi et al., 1997, Obstet Gynecol Clin North Am, 24:235-258) and infertility in 40 to 50% of patients (Ozkan et al., 2008, Ann NY Acad Sci, 1127:92-100, Moradi et al., 2014, BMC Womens Health, 14:123). Unfortunately, there are no currently available accurate serum biomarkers of this disease. Imaging techniques such as ultrasound are unreliable in the diagnosis and staging of endometriosis (Dunselman et al., 2014, Hum Reprod, 29:400-412). Definitive diagnosis of endometriosis is often made only at late stages of the disease by direct visualization of the lesions with laparascopy and confirmation of pathology. A major impediment to successful treatment of endometriosis is the failure of diagnosis at an early stage. A simple blood test for endometriosis-specific biomarkers would offer a more timely and accurate diagnosis of the disease and could lead to earlier treatment intervention. Although there have been considerable efforts to identify such biomarkers (Wang et al., 2012, Clin Chem Lab Med, 50:1423-1428, Jia et al., 2013, Hum Reprod, 28:322-330, Suryawanshi et al., 2013, Clin Cancer Res, 19: 1213-1224), no clear choice for such noninvasive diagnostic tools has been identified… development of new noninvasive diagnostic markers for endometriosis is crucial for early diagnosis and proper treatment and management of the disease. Thus there is a need in the art for improved compositions and methods for noninvasive biomarkers of endometriosis” page 2 lines 7-22 and page 3 lines 1-4). Taylor further teaches assessment of lower abdominal pain according to a VAS scale in women with endometriosis and reports significantly higher pelvic pain levels in women with endometriosis compared to controls (page 61, lines 2-7).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try picking blood from the finite list of possible biological samples to be used in the method of assessing endometriosis taught by Giudice because Taylor teaches that there is a need for non-invasive, i.e. blood-based, biomarkers of endometriosis. Given that endometriosis is a recognized problem in the field affecting 6-10% of women in the general population and 35-50% of women with pain and/or infertility (Giudice paras. 4-5); and given that Taylor suggests that blood-based biomarkers enable early diagnosis and treatment (page 3 lines 1-2), a person having ordinary skill in the art would have been motivated to try picking the blood sample, in order to diagnose endometriosis early and apply treatment. A person having ordinary skill in the art would have had a reasonable expectation of success because Giudice teaches that blood as well as blood fractions or products can be used as the biological sample.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Giudice to include the assessment of lower abdominal pain according to a VAS scale taught by Taylor because Taylor teaches that lower abdominal pain levels are higher in endometriosis patients compared to control patients, i.e. teaches that high pain levels are a biomarker of endometriosis and Giudice is interested in diagnosing endometriosis. Therefore, one would have been motivated to make such a modification in order to confirm that the patient has endometriosis. A person having ordinary skill in the art would have had a reasonable expectation of success given that both Giudice and Taylor teach methods of diagnosing endometriosis and Giudice teaches that pelvic pain is a main clinical symptom of endometriosis.
Claims 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Giudice (US PG Pub No. 20080318237 A1)-Cite No. 1 on IDS (filed on 02/07/2022) in view of Taylor (WO 2018044979 A1) (Cited on PTO-892 9/26/2024) and Cluzeau et al. Haematologica. 2017 Oct 5;102(12):2015–2020. doi: 10.3324/haematol.2016.158857 (“Cluzeau”) (Cited on PTO-892 9/3/2025) as evidenced by MBL, “The principle and method of ELISA” (retrieved online from https://www.mblbio.com/bio/g/support/method/elisa.html on 8/20/2025) (Cited on PTO-892 9/3/2025).
Regarding claims 18-20, Giudice teaches a method of detecting an elevated amount or concentration of S100A9 in a patient (para. 136, “The terms "overexpress", "overexpression", "overexpressed", or "up-regulated" interchangeably refer to a protein or nucleic acid (RNA) that is transcribed or translated at a detectably greater level, usually in an endometrial cell from a woman with endometriosis, in comparison to a cell from a woman without endometriosis” para. 50), a method for measuring the amount of S100A9 in a sample from a patient (para. 136 and para. 50), a non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis (Abstract), comprising: obtaining a sample from the patient, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma (para. 48, para. 52, claim 1), and detecting/measuring the elevated amount or concentration of S100A9 in the sample of the patient by contacting the sample with monoclonal antibodies and detecting the binding between S100A9 and the monoclonal antibodies (“[a]ntibody reagents can be used in assays to detect expression levels of the biomarkers of the invention in patient samples using any of a number of immunoassays known to those skilled in the art” para. 87), wherein the monoclonal antibodies specifically bind to S100A9 (“Antibody" refers to a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen… Antibodies can be polyclonal or monoclonal” para. 73), wherein the measuring comprises incubating the sample of the patient with one or more monoclonal antibodies specifically binding to S100A9, wherein one monoclonal antibody is bound to a solid phase and the other is detectably labeled, thereby generating a complex between the one or more antibodies and S100A9 (“The phrase "specifically (or selectively) binds" when referring to a … antibody… refers to a binding reaction that is determinative of the presence of the …often in a heterogeneous population of proteins or nucleic acids and other biologics. In the case of antibodies, under designated immunoassay conditions, a specified antibody may bind to a particular protein at least two times the background and more typically more than 10 to 100 times background” para. 78, “using any of a number of immunoassays known to those skilled in the art…formation of protein/antibody complexes” para. 87, “The antibodies can be immobilized onto a variety of solid supports” para. 90, “A "label" or a "detectable moiety" is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include 32P, fluorescent dyes, electron dense reagents, enzymes ( e.g., as commonly used in an ELISA)” para. 68), and quantifying the complex thereby quantifying the amount of S100A9 in the sample of the patient (“using any of a number of immunoassays known to those skilled in the art…nephelometry assays, in which the formation of protein/antibody complexes results in increased light scatter that is converted to a peak rate signal as a function of the marker concentration, are suitable for use in the methods of the present invention” para. 87), comparing the measured amount or concentration to a reference, and assessing whether the patient has endometriosis or is at risk of developing endometriosis (Abstract, para. 136). Giudice further teaches immunoassay kits for assessing whether a patient has endometriosis or is at risk of developing endometriosis (“the present invention provides kits for the diagnosis or prognosis of endometriosis” Abstract, “The invention provides compositions, kits and integrated systems for practicing the assays described herein using antibodies specific for the polypeptides or nucleic acids specific for the polynucleotides of the invention” para. 99, para. 136). Giudice further teaches that “[t]here is a need in the art for the identification of molecular differences in the endometrium of women with endometriosis in order to better understand the pathogenesis of this condition” (para. 9).
Giudice fails to teach wherein the sample is body fluid selected from the group consisting of blood, serum and plasma in a manner consistent with anticipation, i.e., there is some picking and choosing involved to arrive at the sample being blood, serum or plasma. Furthermore, Giudice fails to explicitly teach a first monoclonal antibody bound to a solid phase and a second monoclonal antibody that is detectably labeled, wherein the first and second monoclonal antibodies each specifically bind to S100A9 at different and non-overlapping epitopes, and detecting a sandwich complex formed between the first monoclonal antibody, Sl00A9, and the second monoclonal antibody.
Taylor teaches “methods useful for the diagnosis, assessment, and characterization of endometriosis in a subject in need thereof” (Abstract).Taylor also teaches that diagnosis of endometriosis relies on invasive procedures like laparoscopy at late stages of the disease, and thus there is a need for non-invasive blood biomarkers of endometriosis for early diagnosis and treatment (page 2 lines 7-22 and page 3 lines 1-4).
Cluzeau teaches that S100A9 is a pro-inflammatory protein (Title). Cluzeau further teaches that “Human S100A9/MRP14 in patients’ serum and supernatants of the HepG2 cell line was quantified using a CircuLex S100A9/MRP14 enzyme-linked immunosorbent assay (ELISA) Kit (MBL, Nagano, Japan)” (page 2016 col. 1 para. 4 and col. 2 para. 1). Note that the kit taught by Cluzeau is a sandwich ELISA as taught by the instant specification page 34 lines 12-15 (“The concentration of S100A9 in human serum was determined using the Human S100A9/MR14 ELISA kit from CircuLex/MBL (distributed by Biozol Eching, Germany; catalogue number: CY-8062). The kit utilizes the quantitative sandwich ELISA technique”). The instant specification page 34 lines 12-25 discloses that the Circulex kit is a sandwich ELISA that uses two monoclonal antibodies, wherein the first monoclonal antibody is bound to a solid phase and the second antibody is detectably labeled (“The concentration of S100A9 in human serum was determined using the Human S100A9/MR14 ELISA kit from CircuLex/MBL (distributed by Biozol Eching, Germany; catalogue number: CY-8062). The kit utilizes the quantitative sandwich ELISA technique…Microtiter plates are pre-coated with a monoclonal antibody specific for human Sl00A9…100 μL of an enzyme-linked monoclonal antibody specific for S 100A9 is added to the wells”). Also, as evidenced by MBL, the sandwich ELISA inherently forms a complex comprising a first antibody to S100A9, S100A9 (analyte) and the second antibody to S100A9, wherein the second antibody is detectably labeled, wherein the first and second monoclonal antibodies each specifically bind to S100A9 at different and nonoverlapping epitopes (page 2 paragraph 1, see the figure on the top of page 2 showing wherein the first and second antibodies each specifically bind to S100A9 at different and nonoverlapping epitopes). Therefore Cluzeau teaches incubating the sample of the patient with a first monoclonal antibody bound to a solid phase and a second monoclonal antibody that is detectably labeled, wherein the first and second monoclonal antibodies each specifically bind to S100A9 at different and nonoverlapping epitopes, thereby forming a sandwich complex comprising the first monoclonal antibody, S100A9, and the second monoclonal antibody for quantifying S100A9 in a blood sample when teaching the use of the S100A9 Circulex kit for measuring S100A9 in plasma. Cluzeau further teaches that “S100A9 is a ligand for CD33 and the Toll-like receptor (TLR)-4 which, through nuclear factor-kB (NF-kB) activation, regulates the transcription and cellular elaboration of inflammatory cytokines such as TNFα and IL-1b” (page 2016 col. 1 para. 1).
It would have been prima facie obvious to try picking blood from the finite list of biological samples to be used in the methods for measuring S100A9 and diagnose endometriosis taught by Giudice because Taylor teaches that there is a need for non-invasive, i.e. blood-based, biomarkers of endometriosis.. Given that endometriosis is a recognized problem in the field affecting 6-10% of women in the general population and 35-50% of women with pain and/or infertility (Giudice paras. 4-5); and given that Taylor suggests that blood-based biomarkers enable early diagnosis and treatment (page 3 lines 1-2), a person having ordinary skill in the art would have been motivated to try picking the blood sample, in order to diagnose endometriosis early and apply treatment. A person having ordinary skill in the art would have had a reasonable expectation of success because Giudice teaches that blood, blood fractions and products can be used as the biological sample.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Giudice in view of Taylor to rely on a first monoclonal antibody being bound to a solid phase and a second monoclonal antibody being detectably labeled, wherein the first and second monoclonal antibodies each specifically bind to S100A9 at different and non-overlapping epitopes, and detecting a sandwich complex formed between the first monoclonal antibody, Sl00A9, and the second monoclonal antibody taught by Cluzeau because it would have been a simple matter of applying a known technique to a known base method. In this case, both Giudice in view of Taylor and Cluzeau teach measuring S100A9 in a serum sample using monoclonal antibodies, detectable labels and solid supports. Cluzeau simply applies the art-recognized technique of using the solid phase sandwich immunoassay described above. Therefore, a person having ordinary skill in the art would have found it obvious to apply the art-recognized technique of Cluzeau to the base method taught by both Giudice in view of Taylor and Cluzeau. Furthermore, Given that Cluzeau teaches that S100A9 regulates cellular elaboration of inflammatory cytokines and Giudice teaches that endometriosis is associated with elevated levels of inflammatory cytokines, a person having ordinary skill in the art would have been motivated to apply the teachings of Cluzeau to the method taught by Giudice in order to research endometriosis and better understand its pathogenesis, which is a current need in the field. A person having ordinary skill in the art would have had a reasonable expectation of success because Cluzeau teaches a kit for carrying out the measurement from a company “MBL” and both Giudice in view of Taylor and Cluzeau teach S100A9 immunoassay kits.
Claims 24 and 27-35 are rejected under 35 U.S.C. 103 as being unpatentable over Giudice (US PG Pub No. 20080318237 A1)-Cite No. 1 on IDS (filed on 02/07/2022)
Regarding claim 24, Giudice teaches a kit for assessing whether a patient has endometriosis or is at risk of developing endometriosis (“the present invention provides kits for the diagnosis or prognosis of endometriosis” Abstract, para. 136). However, note that the limitation of “for assessing whether a patient has endometriosis or is at risk of developing endometriosis” is a statement directed to the intended use of the claimed kit and does not impart any structural limitations to the kit itself. Therefore, these limitations are not required in order to address the claim over the prior art. Giudice further suggests comprising two or more antibodies that specifically bind to S100A9 (“kits for diagnosing endometriosis … comprising a probe for one or more nucleic acid or protein biomarkers known to be differentially expressed in endometriosis. In one embodiment, the biomarkers are selected from the group consisting of those in Tables 4-6” para. 42, “[t]he invention provides… kits … for practicing the assays described herein using antibodies specific for the polypeptides or nucleic acids specific for the polynucleotides of the invention” para. 99), and wherein at least one of the two or more antibodies is detectably labeled (“Kits for carrying out the diagnostic assays of the invention typically include a probe that comprises an antibody or nucleic acid sequence that specifically binds to polypeptides or polynucleotides of the invention, and a label for detecting the presence of the probe. The kits may include … a cocktail of antibodies that recognize at least two marker proteins listed in Tables 4-6 and 8-11” para. 100, claim 9). Giudice further teaches that “[g]rowth of ectopic endometrial tissues in the pelvic cavity, which is a hallmark of endometriosis, is associated with elevated levels of inflammatory cytokines and increased number of activated macrophages in the peritoneal environment” (para. 165). Giudice further teaches that “[e]ndometriosis affects 6-10% of women in the general population and 35-50% of women with pain and/or infertility” (para. 4).
Giudice fails to teach claim 24 in a manner consistent with anticipation, i.e., there is some picking and choosing involved to arrive at two or more antibodies that specifically bind to S100A9, and wherein at least one of the two antibodies is detectably labeled from the list of endometriosis biomarkers (para. 136).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Giudice to have picked S100A9 as the target to the two or more antibodies wherein at least one of the two or more antibodies is detectably labeled, from the list of endometriosis biomarkers taught by Giudice because Giudice teaches that S100A9 is one out of five genes that is upregulated on endometriosis vs. normal control datasets , i.e. Giudice teaches S100A9 as a possible predictable biomarkers of endometriosis. Given that endometriosis is a recognized problem in the field affecting 6-10% of women in the general population and 35-50% of women with pain and/or infertility, a person having ordinary skill in the art would have been motivated to try picking S100A9 in order to diagnose endometriosis and address the problem in the field. A person having ordinary skill in the art would have had a reasonable expectation of success because Giudice teaches that inflammation is associated with endometriosis and also teaches that S100A9 is involved in inflammatory responses.
Regarding claim 27, Giudice further suggests wherein the two or more antibodies are monoclonal antibodies (“Antibodies can be polyclonal or monoclonal” para. 73).
Regarding claims 28-29, “wherein two or more antibodies bind to S100A9 to form a complex” and “wherein the complex forms in a sandwich assay” fail to limit the claimed antibodies and merely recites the intended use of the kit. Therefore, these are not required in order to address the claim over the prior art.
Regarding claim 30, Giudice further suggests wherein the at least one of the two or more antibodies is detectably labeled with a label selected from fluorescent, chemiluminescent, electrochemiluminescent, radioactive, and/or metal-chelate (“A "label" or a "detectable moiety" is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include 32P, fluorescent dyes, electron dense reagents, enzymes ( e.g., as commonly used in an ELISA)” para. 68).
Regarding claim 31, Giudice further suggests wherein a first antibody is bound to a solid phase (“The antibodies can be immobilized onto a variety of solid supports” para. 90).
Regarding claims 32-35, these further expand on the intended use of the kit. Therefore, these are not required in order to address the claim over the prior art.
Claims 36-40 are rejected under 35 U.S.C. 103 as being unpatentable over Giudice as applied to claim 24 above, and further in view of Cluzeau et al. Haematologica. 2017 Oct 5;102(12):2015–2020. doi: 10.3324/haematol.2016.158857 (“Cluzeau”) as evidenced by MBL, “The principle and method of ELISA” (retrieved online from https://www.mblbio.com/bio/g/support/method/elisa.html on 8/20/2025).
Regarding claim 36, Giudice teaches the kit of claim 24 as discussed above.
Giudice further suggests wherein the at least one of the two or more antibodies is detectably labeled with a label (para. 68). Giudice further teaches that “[t]here is a need in the art for the identification of molecular differences in the endometrium of women with endometriosis in order to better understand the pathogenesis of this condition” (para. 9).
Giudice fails to teach wherein a sandwich complex is formed comprising a first antibody to S100A9, S100A9 (analyte) and the second antibody to S100A9, wherein the second antibody is detectably labeled.
Cluzeau teaches that S100A9 is a pro-inflammatory protein (Title). Cluzeau further teaches that “Human S100A9/MRP14 in patients’ serum and supernatants of the HepG2 cell line was quantified using a CircuLex S100A9/MRP14 enzyme-linked immunosorbent assay (ELISA) Kit (MBL, Nagano, Japan)” (page 2016 col. 1 para. 4 and col. 2 para. 1). Note that the kit taught by Cluzeau is a sandwich ELISA as taught by the instant specification page 34 lines 12-15 (“The concentration of S100A9 in human serum was determined using the Human S100A9/MR14 ELISA kit from CircuLex/MBL (distributed by Biozol Eching, Germany; catalogue number: CY-8062). The kit utilizes the quantitative sandwich ELISA technique”). Also as evidenced by MBL, a sandwich ELISA inherently forms a complex comprising a first antibody to S100A9, S100A9 (analyte) and the second antibody to S100A9, wherein the second antibody is detectably labeled (page 2 paragraph 1). Therefore, the teachings of Cluzeau regarding the use of “CircuLex S100A9/MRP14 enzyme-linked immunosorbent assay (ELISA) Kit (MBL, Nagano, Japan)” inherently provides the sandwich complex formation of S100A9 comprising a first antibody to S100A9, S100A9 (analyte) and the second antibody to S100A9, wherein the second antibody is detectably labeled. Cluzeau further teaches that “S100A9 is a ligand for CD33 and the Toll-like receptor (TLR)-4 which, through nuclear factor-kB (NF-kB) activation, regulates the transcription and cellular elaboration of inflammatory cytokines such as TNFα and IL-1b” (page 2016 col. 1 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Giudice to rely on the sandwich assay technique taught by Cluzeau because it would have been a simple matter of applying a known technique to a known base method. In this case, both Giudice and Cluzeau teach measuring S100A9 in a sample using monoclonal antibodies, detectable labels and solid supports. Cluzeau simply applies the art-recognized technique of using the solid phase sandwich immunoassay described above. Therefore, a person having ordinary skill in the art would have found it obvious to apply the art-recognized technique of Cluzeau to the base method taught by both Giudice and Cluzeau. Furthermore, given that Cluzeau teaches that S100A9 regulates cellular elaboration of inflammatory cytokines and Giudice teaches that endometriosis is associated with elevated levels of inflammatory cytokines, a person having ordinary skill in the art would have been motivated to apply the teachings of Cluzeau to the kit taught by Giudice in order to research endometriosis and better understand its pathogenesis, which is a current need in the field. A person having ordinary skill in the art would have had a reasonable expectation of success because Cluzeau teaches the kit is from a company “MBL” and both Giudice and Cluzeau teach immunoassay kits for S100A9.
Regarding claim 37, Giudice in view of Cluzeau teach the kit of claim 36 as discussed above.
Giudice further suggests wherein the second antibody is detectably labeled with a label selected from fluorescent, chemiluminescent, electrochemiluminescent, radioactive, and/or metal-chelate (para. 68).
Regarding claims 38-40, these are drawn to the intended use of the claimed kit and not explicitly required in order to address the claim over the art.
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.
Claims 1, 18-20, 24 and 27-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 12625146 B2 in view of Giudice.
Regarding claims 1, 18-20, 24 and 27-40, U.S. Patent No. 12625146 B2 recites a non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising measuring the amount or concentration of S100A8 in a sample of the patient, comparing the measured amount or concentration to a reference, and determining that the patient has dysmenorrhea according to a Visual Analog Scale (VAS) scale and/or lower abdominal pain according to a VAS scale, wherein the sample is body fluid selected from the group consisting of blood, serum and plasma, and wherein endometriosis is stage I endometriosis according to the revised American Society for Reproductive Medicine (rASRM) staging or stage II endometriosis according to rASRM staging (claims 1-3 and 11); a method of detecting an elevated amount or concentration of S100A8 in a patient, the method comprising: obtaining a sample from the patient, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma, and detecting the elevated amount or concentration of S100A8 in the sample of the patient by contacting the sample with a first antibody and a second antibody that is detectably labeled, wherein the first and second monoclonal antibodies each specifically bind to S100A8 at different and non-overlapping epitopes, thereby forming a sandwich complex comprising the first monoclonal antibody, S100A8, and the second monoclonal antibody, and quantifying the sandwich complex thereby quantifying the amount of S100A8 in the sample of the patient (claims 1-3 and 13-17); a method for measuring the amount of S100A8 in a sample from a patient, the method comprising: obtaining the sample from the patient, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma, measuring the amount of S100A8 in the sample of the patient, and contacting the sample, or a portion thereof, with a first antibody and a second antibody that is detectably labeled, wherein the first and second monoclonal antibodies each specifically bind to S100A8 at different and non-overlapping epitopes, thereby forming a sandwich complex comprising the first monoclonal antibody, S100A8, and the second monoclonal antibody, and quantifying the sandwich complex thereby quantifying the amount of S100A8 in the sample of the patient (claims 1-3 and 13-17); a non-invasive method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising measuring the amount or concentration of S100A8 in a sample of the patient, wherein the measuring comprises incubating the sample of the patient with a first antibody and a second antibody that is detectably labeled, wherein the first and second monoclonal antibodies each specifically bind to S100A8 at different and non-overlapping epitopes, thereby forming a sandwich complex comprising the first monoclonal antibody, S100A8, and the second monoclonal antibody, and quantifying the complex thereby quantifying the amount of S100A8 in the sample of the patient, comparing the measured amount or concentration to a reference, and assessing whether the patient has endometriosis or is at risk of developing endometriosis, wherein the sample is a body fluid selected from the group consisting of blood, serum, and plasma (claims 1-3 and 13-19) . U.S. Patent No. 12625146 B2 further recites wherein the patient is a human female (claim 7).
U.S. Patent No. 12625146 B2 does not recite S100A9, monoclonal antibodies specific to S100A9, wherein a first monoclonal antibody is bound to a solid phase and a kit thereof.
Giudice teaches a method of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising determining the amount or concentration of S100A9 in a sample of the patient, and comparing the determined amount or concentration to a reference (Abstract, claim 1, paragraph 136). Giudice further suggests a kit for assessing whether a patient has endometriosis or is at risk of developing endometriosis comprising two or more antibodies that specifically bind to S100A9 (para. 42, para. 99), and wherein at least one of the two or more antibodies is detectably labeled (para. 100, claim 9). Giudice further suggests wherein antibodies are monoclonal antibodies (“Antibodies can be polyclonal or monoclonal” para. 73). Giudice further suggests wherein a first antibody is bound to a solid phase (“The antibodies can be immobilized onto a variety of solid supports” para. 90). Giudice further teaches that “[e]ndometriosis affects 6-10% of women in the general population and 35-50% of women with pain and/or infertility” (para. 4). Giudice further teaches that “[t]he main clinical symptoms of endometriosis are pelvic pain, bleeding and infertility” (para. 5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of U.S. Patent No. 12625146 B2 to include the method and kit for measuring S100A9 using monoclonal antibodies specific to S100A9, wherein a first monoclonal antibody is bound to a solid phase taught by Giudice because Giudice teaches S100A9 and S100A8 as inflammatory markers of endometriosis (paragraph 136) and U.S. Patent No. 12625146 B2 teaches S100A8 as a marker of endometriosis. Therefore, one would have been motivated to make such a modification as a simple substitution between two known and equivalent biomarkers for endometriosis. A person having ordinary skill in the art would have had a reasonable expectation of success given that both U.S. Patent No. 12625146 B2 and Giudice teach methods of assessing whether a patient has endometriosis or is at risk of developing endometriosis, comprising determining the amount or concentration of an S100 calcium binding protein in a sample of the patient, and comparing the determined amount or concentration to a reference.
Response to Arguments
Applicant's arguments filed 5/11/2026 have been fully considered but they are not persuasive.
Regarding the 112a written description rejection,
Applicant argues that “Claims 18, 19, and 20 have been amended… These limitations are not merely functional. Each defines a structural or architectural feature of the antibody pair, namely the structural class (monoclonal), the spatial relationship (solid-phase capture and detectable labeling), and the epitope topology (different and non-overlapping epitopes on S100A9)… Claim 24 and its dependents likewise recite structural antibody limitations” (page 7 paras. 2-3).
However, contrary to Applicant’s remark, the added limitations fail to define a structural or architectural feature of the antibodies. Limiting the antibodies to them being monoclonal, bound to a solid phase/label and also limiting them to binding to different and nonoverlapping epitopes on S100A9 fails to define the structure of the antibodies.
Applicant further argues that “The Office characterizes the specification's antibody disclosure as "one example" -namely, the CircuLex/MBL kit. Office Action, p. 5. Respectfully, the specification provides considerably more…First, the specification expressly describes a two-antibody sandwich architecture… Second, the specification expressly requires that the two antibodies in the sandwich format bind to "different, non-overlapping epitopes on an analyte of interest."… Third, the working example at paragraph [0166] discloses two specific monoclonal antibodies: a capture "monoclonal antibody specific for human S100A9" pre-coated on microtiter plates, and an "enzyme-linked monoclonal antibody specific for S100A9" serving as the detection antibody…Fourth, the specification expressly identifies monoclonal antibodies as the preferred class for the claimed methods” (page 7 paras. 4-5 and page 8 paras. 1-5).
However, as mentioned above, limiting the antibodies to them being monoclonal, bound to a solid phase/label and also limiting them to binding to different and nonoverlapping epitopes on S100A9 such to form a sandwich complex fails to define the structure of the antibodies.
Applicant further argues that “First, the claims here are not directed to antibody compositions per se. The claims recite diagnostic methods (Claims 1, 18-20) and a detection kit (Claim 24). The antibodies are recited as detection reagents within a defined assay architecture, not as the invention itself” (page 8 last paragraph).
However, the methods require monoclonal antibodies specific to S100A9, and the detection kit comprises two or more antibodies specific to S100A9, therefore, the recited antibodies are being claimed in terms of their function, i.e. binding to S100A9. Because the antibodies are claimed in terms of their ability to bind to S100A9, the specification must also disclose their structure in order to show possession of the genus of antibodies encompassed by the claim (see rejection above).
Applicant further argues that “Possession of the claimed detection architecture is not merely asserted; it is demonstrated through reduction to practice.” (page 9 para. 3).
However, the reduction to practice disclosed is only one example of the genus of antibodies encompassed by the claims. The example disclosed is that of the Circulex/MBL S100A9 kit (spec. page 34 line 13), which is not considered enough evidence to show possession of the claimed genus of antibodies. Note also, that after a search in the patent and non-patent literature, there appears to be limited public availability regarding the claimed monoclonal antibodies specific for S100A9 in the market before the effective filing date of the claimed invention, therefore, the Circulex kit is not considered enough written description under 112a (see 112a rejection above).
Applicant further argues that “If anti-Sl00A9 detection antibodies were so familiar that their use defeats patent eligibility, then a PHOSITA reading the specification's disclosure of a working sandwich ELISA employing two monoclonal anti-Sl00A9 antibodies binding non-overlapping epitopes would necessarily recognize that the inventors possessed functional anti-Sl00A9 antibodies operating in the disclosed architecture. The Office cannot consistently maintain that the same body of antibody technology is, on the one hand, so routine that any application of it is patent ineligible and, on the other hand, so unpredictable that a working example of the disclosed sandwich format conveys no possession” (paragraph bridging pages 9-10).
However, the fact that the Circulex/MBL S100A9 kit was well-understood, routine and conventional does not meant that this kit demonstrates possession of the genus of antibodies specific to S100A9 encompassed by the claims. In other words, the 101 inquiry is different from the 112a inquiry. For 101, the question is whether the antibodies are well-understood, routine and conventional. In this case, the Circulex/MBL kit for S100A9 (spec. page 34 line 13) appears to be well-understood, routine and conventional as evidenced by Shield-Artin (2012), Ilies (2018), and Cluzeau (2017). However, the inquiry regarding 112a is whether the claimed antibodies specific for S100A9 are fully described and supported by the specification to show a possession of the genus of antibodies encompassed by the claims. In this case, given that the Circulex/MBL kit for S100A9 (spec. page 34 line 13) is the sole example of the claimed antibodies, there is a question regarding Applicant’s possession of the genus of claimed antibodies encompassed by the claims.
Regarding the 101 rejections,
Applicant argues that “The antibody-based detection step in amended Claim 20 imposes meaningful physical limitations that go well beyond data gathering: it requires the formation of a defined immunological complex between two structurally constrained monoclonal antibodies binding non-overlapping epitopes of S100A9. This multi-step clinical workflow, applied to a specifically defined patient population (stage I/II endometriosis) and directed toward a specific clinical output (assessment of endometriosis or risk thereof), integrates any judicial exception into a practical application” (page 12 para. 4).
However, contrary to Applicant’s argument, the added limitation are all insignificant presolution activities that fail to use, rely on or apply the judicial exception such to amount to a practical application thereof.
Applicant further argues that “No prior art reference combines (i) measurement of S100A9 specifically in blood, serum, or plasma (rather than endometrial tissue), (ii) comparison to a reference, (iii) VAS-based clinical assessment of dysmenorrhea or lower abdominal pain (Claim 1 ), and (iv) diagnostic application to stage I or II endometriosis (Claim 1). Likewise, no prior art reference combines blood-based S100A9 measurement using a sandwich format with two monoclonal antibodies binding non-overlapping epitopes with a comparison to a reference and an endometriosis assessment (amended Claim 20)… The specification establishes that the claimed methodology provides a significant technical improvement over the prior art” page 13 paras. 1 and 3).
However, although the additional elements of the claims are not all disclosed in a single reference, the claims are rejected under 101 because they are directed to at least one judicial exception without significantly more. The additional elements of the claims fail to use, rely on or apply the judicial exception such to amount to a practical application thereof and also are all well-understood, routine and conventional (see rejection above).
Applicant further argues that “The Office cites Shield-Artin (2012), flies (2018), Cluzeau (2017), and Giudice as evidence that the additional elements are well-understood, routine, and conventional. Office Action, pp. 11-12. None of these references, however, addresses the claimed diagnostic application, namely blood-based S100A9 measurement specifically for the diagnosis of endometriosis (and particularly early-stage endometriosis)… Giudice likewise does not establish well-understood, routine, and conventional practice for the claimed application. As explained in detail in the § 103 response below, Giudice discloses S100A9 in the context of endometrial tissue mRNA microarray analysis, not blood-based protein measurement,… The need to combine multiple references from different fields and contexts to reconstruct the claimed diagnostic methodology is fundamentally inconsistent with the assertion that the same methodology was well-understood, routine, and conventional” (page 14 para. 4 and page 15 paras. 2-3).
However, the blood-based measurement of S100A9 for the diagnosis of endometriosis describes a judicial exception, which is not patent eligible. Furthermore, as mentioned above, although the additional elements of the claims are not all disclosed in a single reference, each of them is well-understood, routine and conventional (see rejection above for a complete analysis).
Regarding the 103 rejections,
Applicant argues that “As discussed below, these amendments further distinguish the claimed invention from the prior art and require a new combination and motivation analysis that the Office has not conducted” (page 16 para. 4).
Indeed, new grounds of rejection, i.e. new combination and motivation analyses, are set forth above (see rejections above).
Applicant further argues that “The reference to Sl00A9 at Giudice paragraph 136, on which the Office principally relies, appears in a discussion of gene expression in endometrial tissue, where Sl00A9 mRNA is identified in a comparison between Giudice's tissue dataset and a separate tissue dataset (Kao et al. (2003))… The Office's citation to Giudice paragraph [0048] for the proposition that "blood and blood fractions" can be used as a biological sample is unavailing…This boilerplate definitional listing is not an experimental teaching that S100A9 is detectable, measurable, or differentially regulated in blood, serum, or plasma. Giudice provides no experimental data, no protocol, no detection conditions, and no comparative analysis directed to S100A9 measurement in blood, serum, or plasma” (page 17 para. 5 and page 18 para. 1).
However, although Giudice fails to show experimental data, Giudice still suggest the detection of S100A9 in blood for diagnosing endometriosis with a reasonable expectation of success (see rejection above for the complete analysis).
Applicant further argues that “The Office's "obvious to try" rationale, premised on the assertion that Giudice teaches "a finite list of possible predictable biological samples for use in the diagnosis of endometriosis (Office Action, pp. 16, 18), conflates Giudice's definitional listing with an experimental teaching” (page 18 para. 2).
However, new grounds of rejection are set forth above. In short, claim 1 is now rejected over Giudice in view of Taylor with a new obviousness rationale, claims 18-20 are rejected over Giudice in view of Taylor and Cluzeau as evidenced by MBL (see rejections above).
Applicant further argues that “The Office's reliance on Giudice paragraph 136 is further undermined because the disclosure on which paragraph 136 rests is factually inaccurate...Applicant has confirmed that Kao et al. contains no S100A9 data whatsoever… The Office, in the present Office Action, declined to substantively engage with this factual discrepancy, stating that "Giudice clearly suggests that S100A9 is a biomarker of early endometriosis in paragraph 136" and that "Giudice is still suggesting the claimed invention." Office Action, p. 39. With respect, this response misframes the issue. Applicant is not arguing that Kao et al. "teaches away" from Sl00A9. Applicant's position is that Giudice paragraph [0136], on which the entire§ 103 rejection rests, contains a demonstrable factual error: it claims to identify a gene "shared" between two datasets, but one of those datasets contains no data on the identified gene” (page 18 paras. 3-4 and page 19 para. 1).
However, even though Kao fails to teach S100A9, it is a fact that paragraph 136 of Giudice teaches S100A9 as a biomarker of endometriosis and thus provides sufficient evidence for a PHOSITA to recognize as obvious the use of S100A9 as a biomarker of endometriosis. See above for the complete 103 analyses.
Applicant further argues that “Even assuming arguendo that a PHOSITA would have been motivated to look to Giudice to identify a candidate biomarker for endometriosis (which Applicant does not concede), the Office has not established a reasonable expectation of success in arriving at the claimed methods. First, Giudice's work was exclusively tissue-based… Second, the prior art at the time of filing expressly recognized the absence of any reliable non-invasive blood-based test for endometriosis… Third, the Office's reasoning that a PHOSITA would simply pick blood from Giudice's definitional list of biological samples and arrive at the claimed methods is contradicted by the post-priority literature. Gibbons et al. documents the persistent failure of the endometriosis biomarker field to identify a reliable blood-based diagnostic. If the claimed methodology were as predictable as the Office posits, it should have been established practice” (page 19 paras. 2-4 and page 20 paras. 1-2).
However, the fact that there are other references that teach that there are no blood-based tests for endometriosis is not evidence that would suggest to a person having ordinary skill in the art a lack of a reasonable expectation of success based on the teachings of Giudice. Giudice teaches in paragraph 48 that blood is a sample type to be used in the methods for diagnosing endometriosis (see rejection above). One would have a reasonable expectation of success because Giudice teaches that blood as well as blood fractions or products can be used as the biological sample. Furthermore, the fact that S100A9 blood-based diagnosis of endometriosis is not an established practice is not evidence that a person having ordinary skill in the art would not have had a reasonable expectation of success in using S100A9 as a blood biomarker for endometriosis based on the obviousness analysis set forth above (see rejection above).
Applicant further argues that “The Office's "Finite List" Reasoning Is Factually Incorrect”…Selecting one gene out of nearly 2,500, for measurement in a sample type for which the reference provides no experimental data, against a clinical question (early-stage endometriosis diagnosis from a blood sample) for which the reference provides no validated answer, does not fall within KSR' s "obvious to try" rationale…The amendments to Claims 18, 19, and 20 introduce a structural antibody limitation not taught by Giudice. Specifically, the amended claims require a sandwich ELISA architecture employing a first monoclonal antibody bound to a solid phase and a second detectably labeled monoclonal antibody, wherein the two monoclonal antibodies each specifically bind to S100A9 at different and non-overlapping epitopes. Giudice contains no teaching of a sandwich ELISA protocol for quantifying S100A9 protein in blood, serum, or plasma” (page 20 paras. 4-5 and page 21 paras. 1-2).
However, note the new grounds of rejection set forth above over Giudice in view of Taylor (claim 1) and Giudice in view of Taylor and Cluzeau (claims 18-20).
Applicant further argues that “The combination of (i) blood, serum, or plasma S100A9 measurement, (ii) VAS-based assessment of dysmenorrhea or lower abdominal pain, and (iii) application to stage I or II endometriosis according to rASRM staging is not taught or suggested by any single reference, nor by the combination of Giudice and Taylor…The combination, on its own terms, is the product of impermissible hindsight reasoning that uses Applicant's disclosure as a blueprint” (bridging paragraph pages 21-22).
However, contrary to Applicant’s argument, Giudice and Taylor address claim 1 without impermissible hindsight. A proper obviousness analysis is set forth above (see rejection above). In short, Taylor teaches that there is a need in the art for blood-based biomarkers of endometriosis because these would enable early diagnosis and treatment; therefore, it would have been obvious to use blood as a sample type in the method for diagnosing endometriosis using S100A9 suggested by Giudice, i.e. because it would enable early diagnosis and treatment.
Applicant further argues that “The specification demonstrates that the claimed diagnostic methodology provides unexpectedly superior diagnostic performance… This performance was not predictable from the prior art. Giudice provides no performance data for S100A9 in any sample type” (page 22 paras. 2-3).
However, new grounds of rejection are made over Giudice in view of Taylor (claim 1) and Giudice in view of Taylor and Cluzeau (claims 18-20). Based on the obviousness analysis set forth above, the arguments drawn to unexpected results are not persuasive.
Applicant further “respectfully requests that the Office hold the nonstatutory double patenting rejections in abeyance until allowable subject matter has been identified in connection with the resolution of the§ 101, § 112(a), and§ 103 rejections addressed above” (page 24 para. 2).
However, no claim is allowed.
Conclusion
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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
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