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 .
Priority
This application, filed 02/20/2024, claims priority benefits from Provisional Application No. 63486230, filed 02/21/2023. The effective filing date of this application is 02/21/2023, the filing date of Provisional Application No. 63486230.
Election/Restrictions
Claims 26-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group of invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/08/2026.
Claims Status
Amendments filed 06/08/2026 are entered. Claims 1-30 are pending. Claims 26-30 are withdrawn pursuant to a restriction election.
Claims 1-25 are under examination.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 10/01/2024 is/are being considered by the examiner.
Drawings
The petition to accept color drawing filed under 37 CFR 1.84(a)(2), filed 02/20/2024, submitted with the appropriate fee set forth in 37 CFR 1.17(h) on 02/20/2024 was GRANTED in the Petition Decision on 05/09/2024. The drawings submitted with color filed 02/20/2024 are therefore accepted and entered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
The date of creation of the sequencing file received by the Office is 02/20/2024. The date of creation recited in the Specification is 02/14/2024. The date of creation is the date of creation of the sequence listing, i.e. the electronic version of the sequence data that accompanies the application, and is the day the Applicant submits the sequence data to the Office and the Office receives it (automatically, when electronically submitted).
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites measuring and comparing the expression level of at least one “neutrophil extracellular traps (NETs)-associated protein” but then later recites that detecting an expression or overexpression of “neutrophil extracellular traps” relative to the reference sample is indicative of FSHD. The Examiner believes the Applicant submitted a typographical error and intends to recite, as evidenced by the rest of the disclosure and for consistency, that detecting an expression or overexpression of “neutrophil extracellular traps (NETs)-associated protein” relative to the reference sample is indicative of FSHD. This is appropriately recited in claim 13.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites a method for diagnosing or “detecting” Facioscapulohumeral Dystrophy (FSHD) in a subject, wherein the eventual detection of expression or overexpression of NETs relative to the reference sample is “indicative” of FSHD. This implies that “detecting” has the same scope as diagnosing, in that the results indicate FSHD. However, “detecting” and “indicative” is not distinctly defined in the specification, and the commonly understood meaning of “detecting” in the context of pathologies can encompass more than diagnosing while “indicative” implies the pathology is singled out from other potential diagnoses. It is unclear what difference in scope, if any, is meant between “diagnosing” and “detecting” FSHD when the results can be indicative of FSHD.
The claims are hereafter interpreted to mean that detecting is limited to methods that are indicative of FSHD, which is similar in scope to diagnostic.
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 1-25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim(s) recite(s) expression or overexpression of neutrophil extracellular traps (NETs)-associated protein is indicative of FSHD, which is a natural phenomenon. This judicial exception is not integrated into a practical application because the judicial exception is not used to influence the method of treating in a way that is significantly more than what is already known in the art about treating FSHD. The method of detecting the expression of NETs-associated protein is not more than a generalized method stated to measure the expression. Furthermore, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements represent only well-understood, routine, conventional activity, specified at a high level of generality to the judicial exception.
Step 1: Is the claim directed to a process, machine, manufacture, or composition of matter?
Claims 1-25 are directed to a process.
Claims 1-12 are directed to a method for diagnosing or detecting a disease by measuring the expression of NETs-associated protein. Claims 13-25 are directed to a method for treating a subject based on the detection of the disease by measuring the expression of NETs-associated proteins.
Step 2A Prong 1: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
MPEP section 2106.04(b)(I) states:
"… The law of nature and natural phenomenon exceptions reflect the Supreme Court's view that the basic tools of scientific and technological work are not patentable, because the "manifestations of laws of nature" are "part of the storehouse of knowledge," "free to all men and reserved exclusively to none." Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948). …
The courts have identified the following concepts and products as examples of laws of nature or natural phenomena: …
iv. a correlation that is the consequence of how a certain compound is metabolized by the body, Mayo Collaborative Servs. v. Prometheus Labs., 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012);
v. a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017); …
xi. the natural relationship between a patient’s CYP2D6 metabolizer genotype and the risk that the patient will suffer QTc prolongation after administration of a medication called iloperidone, Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals, 887 F.3d 1117, 1135-36, 126 USPQ2d 1266, 1281 (Fed. Cir. 2018). …"
Claim 1 is directed to a method of diagnosing or detecting Facioscapulohumeral Dystrophy (FSHD) by measuring the expression level of at least one NETs-associated protein from a subject, wherein overexpression of the NET-associated proteins are indicative of FSHD.
Claim 13 is a method of treating a subject with a therapeutic agent if the subject is found to have an overexpression of the NET-associated proteins. Claims 6-7 and 16-17, dependent on claim 1 and claim 13, respectively, further recite detecting the expression level of mitochondrial proteins wherein detecting overexpression of a mitochondrial protein is indicative of FSHD. The other dependent claims further limit the subject, type of sample, NETs-associated protein, mitochondrial protein, and class of therapeutic agent.
Heier teaches the correlation between the significant overexpression of the NET-associated protein, calprotectin, and FSHD (Abstract; Heier et al, published 2020). Heier teaches that this correlation is a natural process due to the pathophysiology of the disease (p.13).
Turki teaches that mitochondrial dysfunction and oxidative stress is correlated with the muscle function impairment in FSHD (Abstract; published 2012). Amato teaches that serum levels of GDF-15, a mitochondrial protein, is often elevated in mitochondrial disorders with muscle weakness (p. 3645, col. 2, para. 3; published 2025). Wang teaches that FSHD is associated with ANT1 gene overexpression (published 2020; p. 2, Abstract and p. 6, para. 1) and ANT1 overexpression is, in turn, associated with highly upregulated GDF15 (p. 10, para. 1) (published 2020). In contrast, Poulsen teaches that GDF-15 is also significantly elevated in mitochondrial myopathies subjects compared to healthy controls (e.g. p. 38, Figure 1A; published 2020). However, levels in muscular dystrophy subjects, which included FSHD subjects, was comparable to healthy controls regardless of pathology subgroup (p. 37, Table 2 and p. 38, section: 3.3.2, paras. 1-2), which contradicts the instant disclosure.
Therefore, GDF-15 is unpredictably upregulated in FSHD patients, or upregulated in specific populations/subsets of FSHD; however, if GDF-15 is upregulated in a FSHD patient, it is reasonably likely that it occurs naturally due to the pathophysiology of the disease.
Similar to example (v) above, the correlation between an overexpression of the NET-associated proteins or mitochondrial protein and FSHD is a natural phenomenon.
All other claims depend on independent claims 1 or 13 and therefore also recite a natural phenomenon.
Therefore, claims 1-25 recite a natural phenomenon.
Step 2A Prong 2: If so, does the claim recite additional elements that integrate the judicial exception into a practical application? If the additional elements provide integration into a practical application, then the claim is eligible.
The MPEP provides guidelines for limitations that are not indicative of integration into a practical application, such as:
in MPEP 2106.05(f):
"Adding the words “apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer, or merely uses a computer as a tool to perform an abstract idea";
in MPEP 2106.05(g):
"Adding insignificant extra-solution activity to the judicial exception"; and
in MPEP 2106.05(h):
"Generally linking the use of the judicial exception to a particular technological environment or field of use."
In contrast, the MPEP provides an example for limitations that are indicative of integration into a practical application.
MPEP section 2106.04(b)(I) states:
"… Even if a claim does recite a law of nature or natural phenomenon, it may still be eligible at any of Pathways A through C. For example, claims reciting a naturally occurring relationship between a patient’s genotype and the risk of QTc prolongation (a law of nature) were held eligible as not "directed to" that relationship because they also recited a step of treating the patient with an amount of a particular medication that was tailored to the patient’s genotype. Vanda Pharms., 887 F.3d at 1134-36, 126 USPQ2d at 1279-81. This particular treatment step applied the natural relationship in a manner that integrated it into a practical application. The court’s analysis in Vanda is equivalent to a finding of eligibility at Step 2A Prong Two (Pathway B).
In this case, the method of diagnosing FSHD is simply a generalized instruction to detect the correlation of NETs-associated protein and/or mitochondrial protein expression. However, the method itself amounts to not more than adding the words "apply it" (or an equivalent) to the judicial exception, i.e. apply the correlation between NETs-associated protein expression and FSHD as a method to diagnose FSHD. Regarding the dependent claims, the state of the art already teaches NETs-associated protein, such as calprotectin, (Heier, published 2020; Abstract) and mitochondrial protein, such as GDF-15, (Amato, published 2025; p. 3645, para. 3) is naturally released by cells into bodily fluids, such as blood, and detectable in plasma samples relative to healthy controls. Therefore, the claims do not add anything significantly more to the judicial exception.
Regarding the method of treating, the claims simply recite treating FSHD with a therapeutic agent and then, more specifically, general inhibitors of factors that are correlated with FSHD, such as DUX4, GDF-15, and inflammatory agents. The claims do not recite a treatment step that is tailored to the subject’s expression profile.
Lim teaches the relationship between DUX4 expression and FSDH (Abstract), and teaches DUX4 inhibitor, whether by inhibiting DUX4 at the DNA, RNA, or protein level, is already a treatment strategy option known in the art, and the claims do not recite any more than a generalized instruction to use these classes of DUX4 inhibitors (e.g. Figure 2; published 2021).
Therefore, treating a person with FSHD, who would naturally have NETs-associated protein expression, with these therapeutics amounts does not amount to a practical application. Stemmerik teaches the overexpression of IL-6, a marker of inflammation, is elevated in FSHD compared to healthy controls and correlated with disease severity (p. 368, col. 1, para. 3, published 2025).
Claims 1-25 do not recite additional elements that integrate the judicial exception into a practical application.
Step 2B: If the claim is “directed to” a judicial exception, determine whether any additional element, or combination of additional elements, in the claim is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception.
The MPEP provides guidelines for limitations that are not indicative of "significantly more" than the judicial exception.
MPEP section 2106.05(d) states:
"Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception."
Determining overexpression of a protein that is indicative of a disease by way of obtaining a sample and measuring the overall expression level of NETs-associated proteins and comparing the levels to a reference sample is conventional in the art. The sample being bodily fluid known to contain the expressed protein is routine and well-understood. Therefore, the additional elements do not amount to significantly more than the judicial exception, the known correlation between overexpression of specific proteins and FSHD.
Additional elements added to judicial exception include administering a therapeutic agent to treat a FSHD. Claim 13 generally recites a "therapeutic agent", which is a high level of generality. Dependent claims to the method of treatment claims include specific therapeutics; however, these therapeutics are well-understood to one in the art and they are also specified at a high level of generality without any nuance based on the patient's specific expression. In other words, the measurement of the natural phenomenon does not change the well-understood, routine, and/or conventional therapeutic administration and so this treatment does not add significantly more to the judicial exception.
Claims 1-25 do not recite additional elements that is sufficient to ensure the claim as a whole amounts to significantly more than the judicial exception.
Claim Rejections - 35 USC § 112(a)
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.
Written Description
Claims 1-25 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.
There are two written description problems:
Written description for the genus of NETs-associated protein and mitochondrial proteins being indicative of FSHD.
Written description for expression of NETs-associated protein being indicative of FSHD.
CLAIMED INVENTION:
The claimed invention is directed to measuring the expression level of at least one NETs-associated protein, and then specifically NETs-associated proteins are selected from NE-DNA, MPO-DNA, and calprotectin, from a subject and comparing it to the expression levels in a healthy subject, wherein expression or overexpression of the NET-associated proteins is indicative of FSHD.
The claimed invention is directed to further measuring the expression level of at least one mitochondrial protein from a subject and comparing it to the expression levels in a healthy subject, wherein overexpression of the mitochondrial proteins is indicative of FSHD.
WHAT THE SPECIFICATION TEACHES & THE STATE OF THE ART REGARDING THE ELECTED INVENTION
(A) Regarding the written description for the genus of mitochondrial proteins being indicative of FSHD:
The specification teaches the above method wherein the NETs-associated proteins are selected from NE-DNA, MPO-DNA, and calprotectin (e.g. p. 50, Example 7).
The state of the art teaches S100A8, which is a subunit of calprotectin, as a biomarker for FSHD (Heier, Abstract), and that calprotectin is a NETs-associated protein (Wang 2024, p. 6, Table 1).
The state of the art teaches NETs-associated proteins comprise of more than the instantly claimed proteins (Wang, published 2024; p. 4-6, Table 1).
Regarding the written description for the genus of mitochondrial proteins being indicative of FSHD:
The specification recites the above method wherein the mitochondrial proteins are selected from at least one of fMET, GDF-15, 8-OHdG, and MT-ND6. However, the specification only provides support that GDF-15 is significantly elevated in plasma from subjects with FSHD, and not any of the other mitochondrial proteins (p. 49-50, Example 6; and Figures 21-22).
The state of the art teaches mitochondrial proteins, even more than instantly claimed (Pfanner, published 2019; e.g. Figure 2).
However, the state of the art is silent on whether fMET, 8-OHdG, and MT-ND6 can be used as diagnostic of FSHD.
In summary, the state of the art teaches more NETs-associated protein and mitochondrial proteins than instantly disclosed. However, the state of the art and the instant disclosure together do not distinctly delineate all NETs-associated proteins and mitochondrial proteins into those that are associated with FHSD and those that are not. Furthermore, the disclosure provides support for the claimed NETs-associated proteins but not for all the mitochondrial proteins, besides GDF-15.
Therefore, knowing some NETs-associated proteins and mitochondrial proteins associated with FHSD does not tell one skilled in the art all the NETs-associated proteins and mitochondrial proteins that are and are not associated with FHSD.
(B) Regarding the written description for expression of NETs-associated protein being indicative of FSHD:
The specification teaches overexpression of NETs-associated protein, NE-DNA, MPO-DNA, and sometimes calprotectin, in FSHD. However, Figure 14A and Figure 14B discloses one study where calprotectin is under-expressed in FSHD subjects compared to healthy controls.
Furthermore, the specification teaches that even the control subjects have some “expression” of these NETs-associated protein and mitochondrial proteins (e.g. Figures 14-16 and 21-22).
WHAT WRITTEN DESCRIPTION IS MET BY THE ELECTED INVENTION
Written description is met for the claimed method when the NETs-associated proteins are selected from at least one of NE-DNA, MPO-DNA, and calprotectin.
Written description is met for the claimed method when the mitochondrial proteins is GDF-15.
WHY THE INVENTION LACKS WRITTEN
(A) The disclosure and the state of the art together do not tell the totality of which NETs-associated proteins and mitochondrial proteins within the claimed genus of NETs-associated proteins and mitochondrial proteins are applicable to this claim. The invention lacks written description for the entire genus of NETs-associated proteins, specifically those not instantly claimed, and mitochondrial proteins, specifically those besides GDF-15.
(B) The disclosure shows that NETs-associated proteins, such as NE-DNA, MPO-DNA, and calprotectin are expressed in healthy control subjects that do not have FSHD. Therefore, expression alone of NE-DNA, MPO-DNA, and calprotectin does not have written support for being indicative of FSHD.
CONCLUSION
(A) The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.Since each NETs-associated protein and mitochondrial protein have distinct function from each other, the disclosed species are not representative of the entire genus due to the high variability in the genus. As such the disclosure of these species is insufficient written description for the entire scope of the claimed invention that encompasses the broad genus of NETs-associated proteins, besides those specifically instantly claimed, and mitochondrial proteins, besides GDF-15.
(B) The claimed invention lacks written description for the expression of NETs-associated protein being indicative of FSHD since the disclosure and/or the state of the art shows expression of these proteins in healthy controls and the need for, at least, overexpression compared to a healthy control to be indicative of FSHD.
Enablement
Claims 1-25 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Pursuant to In re Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), the following factors are used to determine whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue":
(A) The breadth of the claims & (B) The nature of the invention
The claims encompass a method of diagnosing or detecting FSHD by a general directive to measure NETs-associated proteins and, in some embodiments, mitochondrial proteins, wherein an overexpression relative to healthy subjects is indicative of FSHD.
The claims further encompass a method of treating a subject with a therapeutic agent, and then specific therapeutic classes, DUX4 inhibitors, anti-inflammatory, or GDF-15 inhibitor, wherein the subject is determined to be suffering from or at risk of FSHD using the previous method of diagnosing or detecting FSHD.
(C) The state of the prior art
Seto teaches that NETs-associated proteins, such as human NE-DNA complexes and MPO-DNA complexes are elevated, as a whole, in the class of pathologies called idiopathic inflammatory myopathies (p. 2, section: Results, para. 1), indicative of skeletal muscle injury (p. 2, section: Results, para. 2; published 2020).
Tulangekar teaches that MPO and NE are also elevated in Duchenne muscular dystrophy (DMD) subjects compared to healthy controls and contribute to the pathogenesis of DMD (Abstract and p. 6, section: 4. Does Myeloperoxidase (MPO) Production Contribute to DMD Pathogenesis? & section: 5. Can Neutrophil Elastase (NE) Be Used as a Target to Improve Muscle Regeneration in DMD?; published 2021).
In summary, these two references teach that elevated NETs-associated proteins/complexes, such as MPO-DNA and NE-DNA are present in other pathologies besides FSHD, and therefore, absent other distinguishing steps in the method, cannot be used to diagnose FSHD.
Regarding the NETs-associated protein, calprotectin, Heier teaches S100-A8, which is a subunit of calprotectin is elevated in FSHD (Abstract), as a biomarker for FSHD (Abstract). Heier does not explicitly indicate detecting overexpression of NETs-associated protein, such as S100-A8, is diagnostic of FSHD, but teaches it is an overexpressed biomarker of FSHD and motivates the further development of S100A8 and calprotectin as a monitoring and pharmacodynamic biomarker for FSHD (Abstract).
Heier further teaches obtaining biological samples from the subject (p. 3, section: 2.2. Patients and Sample Collection), measuring the expression level of the NETs-associated protein S100-A8 (p. 6, section: 2.7. Enzyme-Linked Immunosorbent Assay (ELISA)), and comparing the NETs-associated protein S100-A8 expression levels to the expression levels in a reference sample (“healthy controls”) (p. 6, section: 2.7. Enzyme-Linked Immunosorbent Assay (ELISA)), wherein NETs-associated protein S100-A8 was significantly overexpressed in the FSHD samples compared to the healthy controls (p. 12, para. 1 and Table 4).
Therefore, while the part of the claimed method directed to measuring the NETs-associated protein from blood/serum samples and comparing it to healthy controls to see an elevation is enabled (i.e. the results may indicate elevated levels in FSHD subjects compared to healthy control), the method is not enabling for using these results to diagnose FSHD.
Poulsen teaches that GDF-15 is also significantly elevated in mitochondrial myopathies subjects compared to healthy controls (e.g. p. 38, Figure 1A). However, levels in muscular dystrophy subjects, which included FSHD subjects, was comparable to healthy controls regardless of pathology subgroup (p. 37, Table 2 and p. 38, section: 3.3.2, paras. 1-2), which contradicts the instant disclosure.
In contrast, Wang teaches that FSHD is associated with ANT1 gene overexpression (published 2020; p. 2, Abstract and p. 6, para. 1) and ANT1 overexpression is, in turn, associated with highly upregulated GDF15 (p. 10, para. 1), which encodes the mitochondrial protein, GDF-15 (published 2020), implying that GDF-15 may be elevated in FSHD.
In summary, this reference teaches that elevated GFP-15 levels are present in other pathologies besides FSHD. Additionally, the art and the instant disclosure provides conflicting conclusions regarding GFP-15 levels in FSHD compared to healthy controls, indicating unpredictability in even whether elevated GFP-15 levels is correlated with FSHD, let alone diagnostic of FSHD.
Therefore, elevated NETs-associated proteins alone are not enabling for diagnosing FSHD because they are not unique to FSHD, and even the combination of elevated NE-DNA, MPO-DNA, and GDF-15 is not enabled for diagnosing FSHD because GDF-15 is unpredictably correlated with FSHD.
Regarding the method of treating, Lim teaches the relationship between DUX4 expression and FSDH (Abstract), and teaches DUX4 inhibitor, whether by inhibiting DUX4 at the DNA, RNA, or protein level, is a potential treatment strategy option known in the art (e.g. Figure 2; published 2021). However, it follows that the method of treating FSHD is also not enabled because it uses the preceding method of diagnosing FSHD found to be not enabled.
(D) The level of one of ordinary skill
The invention is directed to a different method of diagnosing a disease than the currently clinically accepted genetic testing. The level needed to diagnose a complex disease is high, requiring a way to not only distinctly differentiate a disease state from healthy controls but the ability to distinguish FSHD specifically from any other pathology.
(E) The level of predictability in the art
The level of predictability in the art is low. Correlation between elevation of the claimed combination of proteins has not been shown to be unique to FSHD. Further, there is no art-recognized or instantly disclosed level of the claimed proteins that are specifically indicative of FSHD over other pathologies with elevated NETs-associated protein and/or mitochondrial proteins.
(F) The amount of direction provided by the inventor
The instant disclosure provides directions to measure the claimed protein levels throughout the Examples. However, since measuring the protein levels alone, without knowing what levels are indicative of FSHD, not just compared to healthy controls but to other pathologies with these elevated proteins, these directions are insufficient to enable the claimed ability to diagnose FSHD.
The instant disclosure recites that GDF-15 levels correlated with FSHD clinical functional outcomes, indicating its potential utility as a biomarker for disease progression (para. 0167); however, this is not the same things as diagnosing, and this use is not within the scope of the claims.
(G) The existence of working examples
The disclosure teaches that there are elevated GFD-15, NE-DNA, MPO-DNA, and likely calprotectin in known FSHD subjects compared to subjects without FSHD. There are no working examples in the disclosure of the claimed protein expression levels used to diagnose FSHD. Elevated levels of these proteins would not diagnose FSHD, i.e. distinguish it from other pathologies marked by elevations of these proteins relative to healthy individuals.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The quantity of experimentation needed to use this invention is high with an unknown likelihood of success.
Mere overexpression or expression of NETs-associated proteins and mitochondrial proteins are not diagnostic of FSHD because it occurs in other pathologies. Even though there are indications in the art that the levels of specific proteins may be different in different pathologies and specifically in different muscular dystrophies, it is unknown whether even these levels can be used to specifically diagnose specific pathologies and the instant disclosure provides no guidance on protein levels. Even the combinations of overexpressed proteins, such as NE-DNA, MPO-DNA, and GDF-15, are likely seen in other pathologies. In other words, there is an unknown likelihood of success. Therefore, a high quantity of experimentation would be needed just to confirm this invention is usable.
Closest Prior Art
The closest prior arts are directed to references that teach the correlations between the claimed proteins and FSHD. The closest prior art also teaches that protein biomarkers can be used to monitor FSHD status in patients and/or response to treatment; or to “detect” FSHD in terms of detecting an early disposition towards FSHD, risk of acquiring FSHD, or FSHD prognosis. However, as stated in the enabling rejection, the art does not teach this correlation can be used to diagnose or detect (i.e. indicate) FSHD.
Chen (Chen et al, WO 2022/098746 A1, The circulating miRNA and protein biomarkers for facioscapulohumeral dystrophy; filed 11/03/2021)
Chen teaches a method for detecting or monitoring FSHD comprising detecting one or more biomarkers, such as micro-RNA and/or protein biomarkers, that are significantly decreased or increased in subjects having FSHD compared to healthy control subjects (Abstract). One of these protein biomarkers is S100A8, which is a subunit of calprotectin (e.g. p. 4, para. 6). Chen distinctly defines “detecting or monitoring FSHD” to encompass prognosis of FSHD and monitoring of already diagnosed FSHD (p. 4, para. 2). Chen teaches that protein biomarkers can be used to monitor FSHD status in patients and/or response to treatment; or to “detect” FSHD in terms of detecting an early disposition towards FSHD, risk of acquiring FSHD, or FSHD prognosis (p. 4, para. 2).
The prior art differs from the instant application because this teaches (1) monitoring FSHD, meaning that the subject is already diagnosed with FSHD, and (2) detecting FSHD, but through the lens of prognosis; i.e. the method does not indicate FSHD nor is diagnostic of FSHD.
Heier (Heier et al, Multi-Omics Identifies Circulating miRNA and Protein Biomarkers for Facioscapulohumeral Dystrophy, Journal of Personalized Medicine, published 2020)
Heier teaches S100-A8, which is a subunit of calprotectin is elevated in FSHD (Abstract), as a biomarker for FSHD (Abstract).
Heier further teaches obtaining biological samples from the subject (p. 3, section: 2.2. Patients and Sample Collection), measuring the expression level of the NETs-associated protein S100-A8 (p. 6, section: 2.7. Enzyme-Linked Immunosorbent Assay (ELISA)), and comparing the NETs-associated protein S100-A8 expression levels to the expression levels in a reference sample (“healthy controls”) (p. 6, section: 2.7. Enzyme-Linked Immunosorbent Assay (ELISA)), wherein NETs-associated protein S100-A8 was significantly overexpressed in the FSHD samples compared to the healthy controls (p. 12, para. 1 and Table 4).
Heier further teaches the reference sample is a biological sample obtained from a healthy subject who is not suffering from or at risk for FSHD (p. 3, section: 2.2. Patients and Sample Collection). Heier teaches the biological sample and/or reference samples are plasma samples (p. 3, section: 2.2. Patients and Sample Collection).
Heier does not explicitly teach detecting overexpression of NETs-associated protein, such as S100-A8, is diagnostic of FSHD, but teaches it is an overexpressed biomarker of FSHD and motivates the further development of S100A8 and calprotectin as a monitoring and pharmacodynamic biomarker for FSHD (Abstract). Heier does not explicitly teach the further detecting of mitochondrial proteins and mitochondrial protein levels being indicative of FSHD.
Wang (Wang et al, Cytosolic Adaptation to Mitochondrial Precursor Overaccumulation Stress Induces Progressive Muscle Wasting, published 2020).
Wang teaches that FSHD is associated with ANT1 gene overexpression (published 2020; p. 2, Abstract and p. 6, para. 1) and ANT1 overexpression is, in turn, associated with highly upregulated GDF15 (p. 10, para. 1), which encodes the mitochondrial protein, GDF-15 (published 2020).
Lim (Lim et al, Genetic Approaches for the Treatment of Facioscapulohumeral Muscular Dystrophy; published 2021).
Lim teaches the relationship between DUX4 expression and FSDH (Abstract), and teaches DUX4 inhibitor, whether by inhibiting DUX4 at the DNA, RNA, or protein level, is a potential treatment strategy option known in the art (e.g. Figure 2; published 2021).
Conclusion
No claims are allowed.
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/BONIRATH CHHAY/Examiner, Art Unit 1645 Monday, July 20, 2026
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 July 28, 2026
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