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.
Withdrawn Objections
The objections to the specification are withdrawn in response to the amendments.
The objections to the claims are withdrawn in response to the amendments.
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 1, 18-20, 24 and 36 are amended; claims 2-17, 21-23 and 25-26 are canceled; claims 1, 18-20, 24 and 27-40 are examined below.
Information Disclosure Statement
The information disclosure statement filed 12/3/2025 is being considered by the examiner.
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 18-19 require a binding agent that specifically binds to S100A9. Claims 20, 24-25 and 27-40 require at least one antibody that specifically binds to S100A9.
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 agents/antibodies that specifically bind S100A9 (“S100A9/MR14 ELISA kit from CircuLex/MBL” page 34 line 13). 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 each genus of claimed agents. 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.
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 one or more antibodies specifically binding to S100A9 thereby generating a complex between the one or more antibodies and S100A9, and quantifying the 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 an antibody 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 machine or apparatus.
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.
Although measurement of S100A9 is performed using an antibody that specifically binds 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. 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.
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.
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).
It would have been obvious to try picking blood from the biological samples taught by Giudice because Giudice teaches a finite list of possible predictable biological samples for use in the diagnosis 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 blood, in order to diagnose endometriosis. 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.
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 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 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 pain levels higher in endometriosis patients than the control group. One would have been motivated to make such a modification in order to receive the expected benefit of quantifying pain as taught by Taylor (page 61, lines 5-7 of Taylor). 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, 24, 27-28, 30-35 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 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 a binding agent and detecting the binding between S100A9 and the binding agent (“[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 binding agent specifically binds 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” para. 73), wherein the measuring comprises incubating the sample of the patient with one or more antibodies specifically binding to S100A9 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), 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 fails to teach claims 18-20 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.
It would have been obvious to try picking blood from the biological samples taught by Giudice because Giudice teaches a finite list of possible predictable biological samples for use in the diagnosis 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 blood, in order to diagnose endometriosis. 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.
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.
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 were upregulated on endometriosis vs. normal control datasets in two separate independent studies. Furthermore, it would have been obvious to try picking S100A9 from the biomarkers taught by Giudice because Giudice teaches a finite list of 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. 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 claim 28, Giudice further suggests wherein two or more antibodies bind to S100A9 to form a complex (para. 78, para. 87).
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 claim 32, Giudice further suggests wherein the endometriosis is selected from the group consisting of peritoneal endometriosis, endometrioma (Table 1, page 13) and deep infiltrating endometriosis (“severe endometriosis” para. 118). Note that deep infiltrating endometriosis is an inherent concept of severe endometriosis as per page 10, lines 1-5 of the instant disclosure. Also note that claim 32 is drawn to the intended use of the claimed kit and not explicitly required in order to address the claim over the art.
Regarding claim 33, the limitation of “wherein the endometriosis is stage I endometriosis according to revised American Society for Reproductive Medicine (rASRM) staging” is drawn to the intended use of the claimed kit and not explicitly required in order to address the claim over the art. Therefore, the teachings of Giudice further addresses the instant claim.
Regarding claim 34, Giudice further suggests wherein the endometriosis is stage II endometriosis according to rASRM staging (para. 136). 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. However, claim 34 is drawn to the intended use of the claimed kit and not explicitly required in order to address the claim over the art.
Regarding claim 35, Giudice further suggests wherein the patient is a human female (“a woman with endometriosis” para. 50). However, claim 35 is drawn to the intended use of the claimed kit and not explicitly required in order to address the claim over the art.
Claims 29 and 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 claims 29 and 36, Giudice teaches the kit of claim 24 as discussed above.
Giudice fails to teach wherein the complex forms in a sandwich assay and 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 Cluzeau suggests that this enables the detection of pro-inflammatory protein S100A9 in the serum of patients. 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 measure S100A9 in serum for its relation to inflammation and endometriosis. 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 (“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 38, Giudice in view of Cluzeau teach the kit of claim 36 as discussed above.
Giudice further suggests wherein the endometriosis is selected from the group consisting of peritoneal endometriosis, endometrioma (Table 1, page 13) and deep infiltrating endometriosis (“severe endometriosis” para. 118). Note that deep infiltrating endometriosis is an inherent concept of severe endometriosis as per page 10, lines 1-5 of the instant disclosure. Also note that claim 38 is drawn to the intended use of the claimed kit and not explicitly required in order to address the claim over the art.
Regarding claim 39, the limitation of “wherein the endometriosis is stage I endometriosis according to revised American Society for Reproductive Medicine (rASRM) staging” is drawn to the intended use of the claimed kit and not explicitly required in order to address the claim over the art. Therefore, the teachings of Giudice in view of Cluzeau further addresses the instant claim.
Regarding claim 40, Giudice in view of Cluzeau teach the kit of claim 36 as discussed above.
Giudice further suggest wherein the endometriosis is stage II endometriosis according to rASRM staging (para. 136). 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. However, claim 40 is 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, 27-28 and 30-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-12, and 14-25 of copending Application No. 17575176 in view of Giudice (US PG Pub No.: 20080318237 A1) Cite No. 1 on IDS (filed on 02/07/2022).
Regarding claims 1, 18-20 and 24, co-pending Application No.17575176 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 (claim 1); 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 binding agent and detecting the binding between S100A8 and the binding agent, wherein the binding agent specifically binds to S100A8 (claim 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 an agent which specifically binds S100A8 (claim 18); 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 one or more antibodies specifically binding to S100A8 thereby generating a complex between the one or more antibodies and S100A8, 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 (claim 19); 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 S100A8, and wherein at least one of the two or more antibodies is detectably labeled (claim 23).
Co-pending application does not recite S100A9.
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).
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 co-pending Application No.17575176 to include the S100A9 limitation taught by Giudice because Giudice teaches S100A9 and S100A8 as inflammatory markers of endometriosis (paragraph 136) and co-pending Application No. 17575176 teaches S100A8. One would have been motivated to make such a modification in order to receive the expected benefit of diagnosing endometriosis as taught by Giudice (Abstract). A person having ordinary skill in the art would have had a reasonable expectation of success given that both co-pending Application No.17575176 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.
Regarding claims 27-28 and 30-31, co-pending Application No.17575176 in view of Giudice address the kit of claim 24 as discussed above.
Co-pending Application No.17575176 fails to recite wherein the two or more antibodies are monoclonal antibodies, wherein the two or more antibodies bind to S100A9 to form a complex, 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, and wherein a first antibody is bound to a solid phase.
Giudice suggests wherein the two or more antibodies are monoclonal antibodies (para. 73 of Giudice), wherein two or more antibodies bind to S100A9 to form a complex (para. 78, para. 87), 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 (para. 68), and wherein a first antibody is bound to a solid phase (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).
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 co-pending Application No.17575176 to rely on the antibodies being monoclonal, wherein two or more antibodies bind to S100A9 to form a complex, wherein 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, and wherein a first antibody is bound to a solid phase taught by Giudice because Giudice teaches a finite list of possible predictable solutions to the problem of assessing endometriosis via antibodies. Given that Giudice teaches that endometriosis is a medical problem affecting 6-10% of women in the general population and 35-50% of women with pain and/or infertility, one would have been motivated to try picking monoclonal antibodies, wherein two or more antibodies bind to S100A9 to form a complex, wherein 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, and wherein a first antibody is bound to a solid phase as the type of antibodies and technique used in the kit for assessing endometriosis. A person having ordinary skill in the art would have had a reasonable expectation of success because both co-pending Application No.17575176 and Giudice teach kits for assessing whether a patient has endometriosis or is at risk of developing endometriosis comprising two or more antibodies that specifically bind to an S100 calcium binding protein, and wherein at least one of the two or more antibodies is detectably labeled.
Regarding claims 32-35, these limitations are drawn to the intended use of the kit and not required in order to address the claim over the art.
Claims 29 and 36-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-12, and 14-25 of copending Application No. 17575176 in view of Giudice (US PG Pub No.: 20080318237 A1) Cite No. 1 on IDS (filed on 02/07/2022) 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 claims 29 and 36, co-pending Application No.17575176 in view of Giudice address the kit of claim 24 as discussed above.
Co-pending Application No.17575176 in view of Giudice fails to recite wherein the complex forms in a sandwich assay and 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. 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 co-pending Application No.17575176 in view of Giudice to rely on the sandwich assay technique taught by Cluzeau because Cluzeau suggests that this enables the detection of pro-inflammatory protein S100A9 in the serum of patients. 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 (para. 136), a person having ordinary skill in the art would have been motivated to apply the teachings of Cluzeau to the kit taught by co-pending Application No.17575176 in view of Giudice in order to measure S100A9 in serum for its relation to inflammation and endometriosis. 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 co-pending Application No.17575176 in view of Giudice and Cluzeau teach immunoassay kits for S100A9.
Regarding claim 37, co-pending Application No.17575176 in view of Giudice and Cluzeau further address wherein the second antibody is detectably labeled with a label selected from fluorescent, chemiluminescent, electrochemiluminescent, radioactive, and/or metal-chelate (para. 68 of Giudice).
Regarding claim 38, co-pending Application No.17575176 in view of Giudice and Cluzeau further address wherein the endometriosis is selected from the group consisting of peritoneal endometriosis, endometrioma (Table 1, page 13 of Giudice) and deep infiltrating endometriosis (“severe endometriosis” para. 118 of Giudice). Note that deep infiltrating endometriosis is an inherent concept of severe endometriosis as per page 10, lines 1-5 of the instant disclosure. Also note that claim 38 is drawn to the intended use of the claimed kit and not explicitly required in order to address the claim over the art.
Regarding claim 39, the limitation of “wherein the endometriosis is stage I endometriosis according to revised American Society for Reproductive Medicine (rASRM) staging” is drawn to the intended use of the claimed kit and not explicitly required in order to address the claim over the art. Therefore, the teachings of co-pending Application No.17575176 in view of Giudice and Cluzeau further addresses the instant claim.
Regarding claim 40 co-pending Application No.17575176 in view of Giudice and Cluzeau address wherein the endometriosis is stage II endometriosis according to rASRM staging (para. 136 of Giudice). 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. However, claim 40 is drawn to the intended use of the claimed kit and not explicitly required in order to address the claim over the art.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 12/3/2025 have been fully considered but they are not persuasive.
Regarding the 112a written description rejection, Applicant argues that “the specification inherently discloses at least two S100A9-specific antibodies in a validated commercial detection system, demonstrating actual possession at the time of filing. With respect to claims 18 and 19, which recite "binding agent," the specification's disclosure of an antibody-based ELISA kit demonstrates possession of binding agents that specifically bind S100A9. In the context of the disclosed immunoassay methodology, a person having ordinary skill in the art (hereinafter, "PHOSITA") would understand that the binding agents employed are the antibodies contained in the CircuLex/MBL kit” (page 10 paras. 1-2). However, although the specification does disclose the CircuLex/MBL kit, this kit alone is not considered sufficient evidence that Applicant was in possession of the genus of binding agents and antibodies that are claimed by function (see 112a rejection above). Applicant further argues that “[t]he Office's own cited references confirm that S100A9-specific antibodies existed and were available to PHOSITA… These references demonstrate that a PHOSITA would recognize from the specification's disclosure of the CircuLex/MBL kit that the inventors possessed antibodies capable of specifically binding S100A9 (page 10 para. 4). However, contrary to Applicant’s remark, a PHOSITA would not have recognized possession of a genus of antibodies or binding agents to S100A9 solely base on the disclosure of the CircuLex/MBL kit. Applicant further argues that “[t]he claims do not seek to encompass every conceivable antibody that could theoretically bind S100A9. Rather, the claims are directed to antibodies that "specifically bind to S100A9" for use in detection methods” (page 11 para. 3). However, contrary to Applicant’s argument, the claims recite “a binding agent…the binding agent specifically binds S100A9” (claim 18), “an agent which specifically binds S100A9” (claim 19), “one or more antibodies specifically binding to S100A9” (claim 20), “two or more antibodies specifically binding to S100A9” (claim 24), “the two or more antibodies are monoclonal antibodies” (claim 27); therefore, the claims are not limited to a specific antibody or agent and read on every conceivable antibody or agent that could theoretically bind specifically S100A9. The claims as currently recited encompass a genus of binding agents and antibodies that are claimed by their function, i.e. specifically binding to S100A9. Applicant further argues that “Applicant respectfully directs the Office's attention to the examination of related application Serial No. 17/575,176 (attorney docket no.: ROCHE-138), which is directed to S100A8, a closely related S100 calcium-binding protein. In that application, the specification similarly disclosed only one species of antibody (a CircuLex/MBL ELISA kit). The Examiner in that application, applying the same legal standards under 35 U.S.C. § l 12(a), concluded: "Sl00A8 is a well-known protein and numerous antibodies specific for detection of this target protein have been developed and published in patents and non-patent literatures, thus the ONE species antibody specific for Sl00A8 satisfies written description under 35 USC 112, first paragraph because sufficient legal representative species." Final Office Action (June 11, 2025), p. 10.” (page 12 para. 1). However, the application under examination is 17575120. Applicant further argues that “Sl00A9 is a thoroughly characterized protein with decades of research, known structure, and established immunogenic properties” (page 13 para. 3). However, although S100A9 is a well-known protein, the claims recite agents and antibodies that bind to S100A9 and the specification does not disclose sufficient description of the structure of said agents and antibodies. Thus, the claims fail to comply with the written description requirement and the rejection under 112a is maintained.
Regarding the 101 rejections, Applicant argues that “(1) determining that the patient has dysmenorrhea and/or lower abdominal pain according to a Visual Analog Scale (VAS), (2) measuring S100A9 specifically in a body fluid selected from blood, serum, or plasma, and (3) assessing specifically stage I or stage II endometriosis according to rASRM staging… Claim 20 similarly requires specific methodology: incubating the sample with one or more antibodies specifically binding to Sl00A9, thereby generating an antibody-Sl00A9 complex, and quantifying that complex to determine the amount of Sl00A9…These specific limitations transform the claims from abstract correlations into practical diagnostic methods directed to particular clinical applications” (page 14 paras. 3-5). However, determining that the patient has dysmenorrhea and/or lower abdominal pain according to a Visual Analog Scale and incubating the sample with one or more antibodies specifically binding to Sl00A9, thereby generating an antibody-Sl00A9 complex is insignificant presolution activity. Also, measuring S100A9 specifically in a body fluid selected from blood, serum, or plasma, assessing specifically stage I or stage II endometriosis according to rASRM staging, and determining the amount of S100A9, is part of at least one the judicial exception (correlation between S100A9 and endometriosis). See rejection above. Applicant further argues that “The Office cites Shield-Artin (2012), Ilies (2018), and Cluzeau (2017) to establish that S100A9 detection was "well-understood, routine and conventional."… They do not establish that the diagnostic application claimed here-using S100A9 as a blood-based biomarker specifically for endometriosis diagnosis, particularly early-stage (stage 1/11) endometriosis-was routine or conventional” (page 15 para. 5). However, using S100A9 as a blood-based biomarker specifically for endometriosis diagnosis, particularly early-stage (stage 1/11) endometriosis is not an additional element that may add significantly more to the judicial exception, it is directed to the judicial exception itself (see rejection above). Applicant further argues that “Giudice's paragraph 136 and Table 6 purport to show genes "shared" between Giudice's moderate/severe endometriosis study and Kao et al.'s minimal/mild endometriosis study… However, Sl00A9 does not exist anywhere in Kao et al.'s study. A complete review of Kao et al.'s Tables 2 and 3, which catalog all 206 differentially expressed genes, reveals only Sl00E (100-fold down-regulated in Table 3), with no mention of Sl00A9 or any other Sl00A9 data. This factual discrepancy renders Giudice' s comparative analysis unreliable and calls into question whether Sl00A9 detection for endometriosis was actually established in the prior art” (page 16 paras. 2-3). However, Giudice is evidence of record that indicates 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 (see rejection above). Applicant further argues that “[t]his persistent failure across the entire research community continuing years after the priority date-demonstrates that successful blood-based detection for endometriosis represented a significant technical challenge at the time of filing, not routine activity that any skilled artisan could accomplish…since S100A9 is an inflammatory biomarker and the claims target stage 1/11 endometriosis, the claimed invention addresses a well-recognized technical obstacle that the prior art did not solve.” (page 17 paras. 4, 6). However, as stated above, the diagnosis of early endometriosis using S100A9 levels from a blood sample is directed to a judicial exception (the natural occurring levels of S100A9 and disease). The correlation itself therefore cannot form the basis for eligibility (see rejection above). Applicant further argues that “the claimed invention achieved unexpected results” (page 18 para. 1). However, the claims are not eligible because they are directed to at least one judicial exception without significantly more (see rejection above). Applicant further argues that “Here, the "significantly more" is not the S100A9 detection step itself, but the discovery that Sl00A9 serves as an effective blood-based biomarker for early-stage endometriosis-a discovery that solved an unmet medical need that the field had struggled with for decades” (page 18 para. 7). However, as stated above, the discovery of a natural correlation between S100A9 and early endometriosis is not patent eligible (see rejection above). Applicant further argues that “[t]he claims do not merely recite a natural correlation; they specify particular clinical assessments (VAS scale), sample types (blood, serum, plasma), detection methodologies (antibody-based immunoassay), and disease staging (stage 1/11 rASRM) that together constitute a specific diagnostic protocol” (page 19 para. 1). However, as stated above, clinical assessments (VAS scale) and generic antibody-based detection methodologies are insignificant presolution activity. Also, the sample type (blood, serum, plasma) and disease stage is part of the judicial exception (see rejection above).
Regarding the 103 rejections, Applicant argues that “S100A9 does not exist anywhere in Kao et al.'s study. A complete review of Kao et al.'s Tables 2 and 3, which catalog all 206 differentially expressed genes identified in that study, reveals only S100E (100-fold down-regulated in Table 3). There is no mention of S100A9, Sl00A8, or any data that could support S100A9 as a "shared" gene between the two datasets. This factual discrepancy renders Giudice's comparative analysis fundamentally unreliable. Applicant raised this issue in the prior response. The Office responded that "[t]he absence of a teaching of S 100A9 from Kao is not sufficient evidence to teach away from the teachings of Giudice regarding Sl00A9 and stage II endometriosis." Office Action, p. 40. This response mischaracterizes Applicant's argument. Applicant is not arguing that Kao et al. "teaches away" from S100A9. Rather, Applicant submits that Giudice' s Table 6 is factually incorrect: it claims to show genes "shared" between two datasets, but one of those datasets contains no S100A9 data whatsoever. The comparative analysis upon which the Office relies simply cannot be accurate… Without accurate characterization of what the prior art actually teaches, there is no valid basis for finding that S100A9 as a blood biomarker for stage 1/11 endometriosis would have been obvious” (page 21 paras. 2-3 and 6). However, Giudice clearly suggests that S100A9 is a biomarker of early endometriosis in paragraph 136. Based on the teachings of Giudice, a person having ordinary skill in the art would have found it obvious to use S100A9 as a blood biomarker of early endometriosis (see rejection above). Although Applicant argues that the teachings of Giudice are not accurate, Giudice is still suggesting the claimed invention. Furthermore, even if Kao fails to teach “S100A9”, this is not enough evidence to show that it would not have been obvious to use S100A9 as a biomarker of early endometriosis as suggested by Giudice. The teachings from the Kao reference, or lack thereof, would not suggest to a PHOSITA to not use the teachings of Giudice or to question the enablement or the accuracy of the teachings of Giudice (see rejection above for the obviousness analysis). Applicant further argues that “Giudice provides no motivation to measure S100A9 in blood samples” (page 22). However, Giudice does provide motivation to measure S100A9 in blood samples (see rejection above). Applicant further argues that “a PHOSITA would not have had a reasonable expectation of success” (page 23). However, as stated in the rejection above, a PHOSITA would have had a reasonable expectation of success (see rejection above). Applicant further argues that “the claimed invention achieved unexpected results” (page 24). However, this is not a persuasive argument given that Giudice suggests S100A9 as a blood biomarker for early endometriosis (see rejection above). Applicant further argues that “the secondary references do not cure the deficiencies in Giudice” (page 25). However, given that Giudice suggests S100A9 as a blood biomarker for early endometriosis, there are no deficiencies in Giudice.
Finally, regarding the double patenting rejections, Applicant argues that “these provisional rejections be revisited once the substantive rejections under 35 U.S.C. §§ 101, 112, and 103 have been resolved” (page 26 para. 6). However, the rejections under 101, 112 and 103 are maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/Fernando Ivich/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678