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 .
Status of Claims
Claims 7, 11, 21-26, and 29-30 are cancelled.
Claims 1-6, 8-10, 12-20, and 27-28 are pending and examined herein.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Based on the filing receipt, the effective filing date of this application is October 29, 2021 which is the filing date of Foreign Application Number (EPO) 21306520.4 from which the benefit of priority is claimed.
Information Disclosure Statement
The information disclosure statement (IDS) filed 08/26/2024 has been considered by the examiner.
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 1-6, 8-10, 12-20, and 27-29 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
Claims 1-6, 8-10, 12-20, and 27-29 are directed to methods and a kit for detecting extracellular traps (ETs), chromatin fragments, and/or nucleosomes in a body fluid sample, e.g., by using antibodies capable of specific binding to ETs, chromatin fragments, and/or nucleosomes. The only limitations placed on the antibodies are that they are capable of specific binding to ETs, chromatin fragments, and/or nucleosomes and that they cause agglutination or precipitation upon binding.
Although independent claim 1 does not require any specific binding reagents, the scope of the claims covers methods and kits using a large genus of binding reagents, e.g., antibodies characterized by substantial variability.
Regarding the predictability or unpredictability in the art, the state of the art attests to the ambiguity of antibody specificity. Antibodies can often be functionally promiscuous or multi-specific which can lead to antibodies binding to more than one antigen, as evidenced by Jain (“Antibody specificity and promiscuity”, published 2019-02-05). Due to multi-specificity and challenges related to specificity, antibodies function with a level of unpredictability that requires the applicant to provide evidence that they have considered a sufficient number of antibodies.
The specification only discloses actual reduction to practice of two antibodies having the necessary functional characteristics. On p. 25-26, the applicant discloses, “Agglutination was achieved using a combination of two different antibodies coated to latex particles. A first antibody was directed to bind to nucleosomes containing histone H3 isoform H3.1 (H3.1-nucleosomes) at an epitope that occurs near to amino acid 30 of H3 and was directly coated to latex particles (size 0.2μm). A second antibody was directed to bind to a nucleosome conformational epitope only present in intact nucleosomes containing histones and DNA and was biotinylated and indirectly attached to Neutravidin coated latex particles (0.3μm)” (see, para. spanning p. 25-26). The specification only further suggests prophetic examples of antibodies capable of specific binding to ETs, chromatin fragments, and/or nucleosomes.
The disclosure of general methods that might be used to test antibody binding fragments is insufficient to describe the claimed genus of antibodies. The Federal Circuit addressed an analogous situation in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004), finding that disclosure of “assays for screening compounds, including peptides, polynucleotides, and small organic molecules to identify those that inhibit the expression or activity of the PGHS-2 gene product,” did not satisfy the written description requirement for claims requiring administration of a “compound that selectively inhibits PGHS-2.” Rochester, 119 F.3d at 918, 927; see also Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company, 598 F.3d 1336, 1344 (Fed. Cir. 2010) (recognizing distinction between requirements for written description and enablement).
Furthermore, there is also no disclosure of any partial structure common to the members of the genus of antibodies that would correlate with function (in this case, the claimed function of having binding specificity to ETs, chromatin fragments, and/or nucleosomes).
The importance of structure/function correlations was recently highlighted by the courts (Abbvie Deutschland v. Janssen Biotech and Centocor Biologics, App. No. 2013-1338, -1346 (Fed. Cir., July 1, 2014)). The Abbvie case involved antibodies and written description. The court stated: “We have held that “a sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568– 69).”. The courts then further stated: “With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” (emphasis added) and then state: " 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. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002).
One skilled in the art would not envision the applicant as in possession of the entire genus of antibodies as claimed since the specification merely suggests prophetic examples in addition to the two examples given.
There is no partial structure or other identifying characteristics disclosed, common to the members of the genus of antibodies having sufficiently high binding specificity for ETs, chromatin fragments, and/or nucleosomes that would allow one skilled in the art to envision that the applicant has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus.
For all of these reasons, the specification does not demonstrate possession of the entire genus of antibodies capable of specific binding to ETs, chromatin fragments, and/or nucleosomes.
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, 19-20, and 27 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 “using a homogeneous immunoassay (HIA) method” (lines 3-4) and “using results obtained” (line 5). It is unclear how the HIA method and results are used.
Claim 19 recites “using the method of claim 1” (line 4) and “using any changes in the concentration” (line 6). It is unclear how the method of claim 1 and changes in the concentration are used.
Claim 20 recites “using the method of claim 1” (line 4) and “using the concentration” (line 6). It is unclear how the method of claim 1 and the concentration are used.
Claim 27 recites “using the method of claim 1” (liens 4-5) and “using the concentration” (line 6). It is unclear how the method of claim 1 and the concentration are used.
See MPEP 2173.05(q). Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. For example, a claim which read: "[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon" was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986).
Although a claim should be interpreted in light of the specification disclosure, it is generally considered improper to read limitations contained in the specification into the claims. See In re Prater, 415 F.2d 1393, 162 USPQ 541 (CCPA 1969) and In re Winkhaus, 527 F.2d 637, 188 USPQ 129 (CCPA 1975), which discuss the premise that one cannot rely on the specification to impart limitations to the claim that are not recited in the claim.
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 19-20 and 27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Under the MPEP, 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.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Natural Laws:
Claim 19 recites, “A method of monitoring the progress of a disease in a subject,
comprising: […] using any changes in the concentration of ETs, chromatin fragments and/or
nucleosomes to monitor the progression of the disease in the subject”. Claim 20 recites, “A method of assigning a risk of an adverse outcome to a subject suffering from an infection, comprising: […] using the concentration of ETs, chromatin fragments and/or nucleosomes detected to assign the likelihood of an adverse outcome to said subject, wherein a subject identified with a high likelihood of an adverse outcome is assigned for medical intervention”. Claim 27 recites, “A method of detecting a subject in need of medical treatment for sepsis or septic shock, comprising: […] using the concentration of ETs and/or chromatin fragments and/or nucleosomes as an indicator that the subject is in need of medical treatment for sepsis or septic shock”.
The claims are directed to the natural relationship/correlation between the concentration of ETs and/or chromatin fragments and/or nucleosomes and a subject in need of medical treatment for sepsis or septic shock, the progress of a disease in a subject, or risk of an adverse outcome to a subject suffering from an infection.
The natural correlation set forth above is considered a judicial exception/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 biomarkers 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 concentration of ETs and/or chromatin fragments and/or nucleosomes and a subject in need of medical treatment for sepsis or septic shock, the progress of a disease in a subject, or risk of an adverse outcome to a subject suffering from an infection. The concentration of ETs and/or chromatin fragments and/or nucleosomes correlate with a subject in need of medical treatment for sepsis or septic shock, the progress of a disease in a subject, or risk of an adverse outcome to a subject suffering from an infection without any human action.
The relationships between the concentration of ETs and/or chromatin fragments and/or nucleosomes and a subject in need of medical treatment for sepsis or septic shock, the progress of a disease in a subject, or risk of an adverse outcome to a subject suffering from an infection are judicial exceptions as they exist in principle apart from any human action; the relationships themselves therefore cannot form the basis for eligibility.
Abstract Ideas:
Claim 19 is directed to “using any changes in the concentration of ETs, chromatin fragments and/or nucleosomes to monitor the progression of the disease in the subject”. Claim 20 is directed to “using the concentration of ETs, chromatin fragments and/or nucleosomes detected to assign the likelihood of an adverse outcome to said subject, wherein a subject identified with a high likelihood of an adverse outcome is assigned for medical intervention”. Claim 27 is directed to “using the concentration of ETs and/or chromatin fragments and/or nucleosomes as an indicator that the subject is in need of medical treatment for sepsis or septic shock”.
The claim limitations of using changes in concentration to monitor disease progression, assigning the likelihood of an adverse outcome, or indicating a subject in need of medical treatment may be categorized as abstract ideas, namely mental processes/concepts performed in the human mind. The claims, under its broadest reasonable interpretation, covers performance of monitoring diseases, assigning likelihood, or indicating a subject solely within the human mind, or by a human using pen and paper. Therefore, these represent abstract ideas.
Step 2A, Prong 2
The above-discussed steps of using changes in concentration to monitor disease progression, assigning the likelihood of an adverse outcome, or indicating a subject in need of medical treatment are insufficient to integrate the judicial exception 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, using changes in concentration to monitor disease progression, assigning the likelihood of an adverse outcome, or indicating a subject in need of medical treatment represent judicial exceptions and not practical applications thereof.
Claims 19-20 and 27 also recite, “(i) detecting a concentration of ETs, chromatin fragments and/or nucleosomes in a body fluid sample”. Claim 19 recites, “repeating step (i) on one or more occasions”. Such steps of detecting a concentration of ETs, chromatin fragments, and/or nucleosomes are insufficient to integrate the judicial exceptions 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).
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
Claims 19-20 and 27 have no other additional elements.
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exceptions.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 5-6, 8-9, 12-15, 19, and 28 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Micallef (US 9400276 B2, published 2016-07-26).
With respect to claims 1 and 8, Micallef teaches a method of detecting extracellular traps (ETs), chromatin fragments and/or nucleosomes in a body fluid sample, comprising:
analyzing the body fluid sample using a homogeneous immunoassay (HIA) method, and
using results obtained from said analyzing to determine a concentration of ETs, chromatin fragments and/or nucleosomes in the body fluid sample (see, e.g., col. 6, lines 4-15: “According to a second aspect of the invention there is provided a method for detecting the presence of a nucleosome containing a histone variant or histone isoform in a sample which comprises the steps of: (i) contacting the sample with a binding agent which binds to the histone variant or histone isoform; (ii) detecting or quantifying the binding of said binding agent to the histone variant or histone isoform in the sample; and (iii) using the presence or degree of such binding as a measure of the presence of nucleosomes containing the histone variant or histone isoform in the sample”, and col. 19, lines 60-63: “the invention a histone variant contained within a nucleosome is detected directly in a biological fluid including blood, plasma, serum and urine by use of an immunoassay method for a histone variant”, and col. 21, lines 57-61: “The immunoassays of the invention include immunometric assays employing […] immunoturbidimetric assays”). It is understood that the immunoturbidimetric assays are homogeneous immunoassays based on claim 8.
With respect to claim 2, Micallef teaches wherein the HIA method comprises:
(a) mixing the body fluid sample with a solution of one or more antibodies, wherein
said antibodies are capable of specific binding to ETs, chromatin fragments and/or nucleosomes and cause agglutination or precipitation upon binding; and
(b) measuring a degree of agglutination or precipitation in the mixture;
wherein the measurement said measuring in step (b) is used to determine the concentration of ETs, chromatin fragments and/or nucleosomes in the body fluid sample (see, e.g., col. 21, lines 57-61: “The immunoassays of the invention include immunometric assays employing […] immunoturbidimetric assays”). The applicant’s specification discloses that the immunoturbidimetric assay of Micallef meets the limitations of claim 2 (see, the para. spanning p. 5-6 of the applicant’s specification).
With respect to claim 5, Micallef teaches wherein the degree of agglutination or precipitation is measured by transmittance (see, e.g., col. 21, lines 57-61: “The immunoassays of the invention include immunometric assays employing […] immunoturbidimetric assays”). The applicant’s specification discloses that the immunoturbidimetric assay of Micallef meets the limitations of claim 5 (see, the para. spanning p. 5-6 of the applicant’s specification).
With respect to claim 6, Micallef teaches wherein the antibody is monoclonal (see, e.g., col. 20, lines 7-8: “The antibody can be a monoclonal antibody or a fragment thereof capable of specific binding to the biomarker”).
With respect to claim 9, Micallef teaches wherein the body fluid sample is blood, serum, or plasma (see, e.g., col. 22, lines 3-6: “In one embodiment, said biological sample comprises a body fluid. For example, biological samples that may be tested in a method of the invention include cerebrospinal fluid (CSF), whole blood, blood serum, plasma”).
With respect to claim 12, Micallef teaches wherein the ETs comprise neutrophil extracellular traps (NETs) (see, e.g., col. 6, lines 4-15: “According to a second aspect of the invention there is provided a method for detecting the presence of a nucleosome containing a histone variant or histone isoform in a sample which comprises the steps of: (i) contacting the sample with a binding agent which binds to the histone variant or histone isoform; (ii) detecting or quantifying the binding of said binding agent to the histone variant or histone isoform in the sample; and (iii) using the presence or degree of such binding as a measure of the presence of nucleosomes containing the histone variant or histone isoform in the sample”, and col. 19, lines 60-63: “the invention a histone variant contained within a nucleosome is detected directly in a biological fluid including blood, plasma, serum and urine by use of an immunoassay method for a histone variant”, and col. 21, lines 57-61: “The immunoassays of the invention include immunometric assays employing […] immunoturbidimetric assays”). The applicant’s specification discloses that assays for NETs include nucleosomes, a component of NETs (see, p. 1, last para. of the applicant’s specification).
With respect to claim 13, Micallef teaches wherein the nucleosome comprises an epigenetic feature of a cell free nucleosome and the one or more antibodies are capable of specific binding to the epigenetic feature of the cell free nucleosome (see, e.g., col. 5, lines 14-15: “Histone variants (also known as histone isoforms) are also known to be epigenetic regulators of gene expression”, and col. 5, lines 57-59: “Surprisingly we have shown that high levels of intact nucleosomes comprising specific histone variants can be detected in plasma and serum samples”).
With respect to claim 14, Micallef teaches wherein the epigenetic feature is a histone isoform or a histone post translational modification (PTM) (see, e.g., col. 10, lines 33-37: “It will be clear to those skilled in the art that inclusion of tests for nucleosomes containing different or additional histone variants or histone modifications or nucleotides would be likely to improve the discrimination of differential diagnosis using such patterns”).
With respect to claim 15, Micallef teaches wherein the histone PTM is a histone PTM
of a core nucleosome (see, e.g., col. 11, lines 3-5: “We have found that high levels of cell free nucleosome associated H2AZ, mH2A1.1 and P-H2AX(Ser139) were detectable by the method of the invention”). The applicant’s specification discloses, “The histone PTM may be a histone PTM of a core nucleosome, e.g. H3, H2A” (see, p. 10, para. 1).
With respect to claim 19, Micallef teaches a method of monitoring the progress of a disease in a subject, comprising:
(i) detecting a concentration of nucleosomes in a body fluid sample obtained from a subject using the method of claim 1 (see above)
(ii) repeating step (i) on one or more occasions; and
(iii) using any changes in the concentration of nucleosomes to monitor the progression of the disease in the subject (see, e.g., col. 21, lines 7-11: “Methods of detecting, monitoring and of diagnosis according to the invention are useful to confirm the existence of a disease, to monitor development of the disease by assessing onset and progression, or to assess amelioration or regression of the disease”, and col. 22, lines 14-21: “the method of the invention is repeated on multiple occasions. This embodiment provides the advantage of allowing the detection results to be monitored over a time period. Such an arrangement will provide the benefit of monitoring or assessing the efficacy of treatment of a disease state. Such monitoring methods of the invention can be used to monitor onset, progression, stabilisation, amelioration, relapse and/or remission”).
With respect to claim 28, Micallef teaches a kit for measuring the concentration of nucleosomes in a body fluid sample comprising: a reagent solution comprising one or more antibodies capable of specific binding to nucleosomes and a container suitable for use in a means to measure the degree of agglutination or precipitation caused upon antibody binding to determine the concentration of nucleosomes (see, e.g., col. 25, lines 11-21: “Diagnostic kits for the diagnosis and monitoring of the presence of a disease state are described herein. In one embodiment, the kits additionally contain a biosensor capable of identifying and/or quantifying a biomarker. Suitably a kit according to the invention may contain one or more components selected from the group: a ligand binder, or ligands, specific for the biomarker or a structural/shape mimic of the biomarker, one or more controls, one or more reagents and one or more consumables; optionally together with instructions for use of the kit in accordance with any of the methods defined herein”).
Claims 1-2, 5-6, 8-10, 12-16, 19-20, and 27-28 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Singapore Volition Pte. Limited (US 9222937 B2, published 2015-12-29, referred hereto as Volition).
With respect to claims 1 and 8, Volition teaches a method of detecting extracellular traps (ETs), chromatin fragments and/or nucleosomes in a body fluid sample, comprising:
analyzing the body fluid sample using a homogeneous immunoassay (HIA) method, and
using results obtained from said analyzing to determine a concentration of ETs, chromatin fragments and/or nucleosomes in the body fluid sample (see, e.g., col. 6, lines 13-25: “According to a second aspect of the invention there is provided a method for detecting nucleosomes in a sample which comprises the steps of: (i) contacting the sample with a first binding agent which binds to nucleosomes; (ii) contacting the nucleosomes or sample with two or more second binding agents which bind to different or separate nucleosome epitopes; (iii) detecting or quantifying the binding of said multiple second binding agents to nucleosomes in the sample; and (iv) using the presence or degree of such binding as a measure of the presence of nucleosomes in the sample”, and col. 5, lines 53-56: “We now report simple immunoassay methods for the direct estimation of nucleosome associated 5-methyl cytosine and 5-hydroxymethyl cytosine DNA methylation in biological samples without extraction”, and para. spanning col. 15-16: “The immunoassays of the invention include immunometric assays employing […] immunoturbidimetric assays”). It is understood that the immunoturbidimetric assays are homogeneous immunoassays based on claim 8.
With respect to claim 2, Volition teaches wherein the HIA method comprises:
(a) mixing the body fluid sample with a solution of one or more antibodies, wherein
said antibodies are capable of specific binding to ETs, chromatin fragments and/or nucleosomes and cause agglutination or precipitation upon binding; and
(b) measuring a degree of agglutination or precipitation in the mixture;
wherein the measurement said measuring in step (b) is used to determine the concentration of ETs, chromatin fragments and/or nucleosomes in the body fluid sample (see, e.g., para. spanning col. 15-16: “The immunoassays of the invention include immunometric assays employing […] immunoturbidimetric assays”). The applicant’s specification discloses that the immunoturbidimetric assay of Volition meets the limitations of claim 2 (see, the para. spanning p. 5-6 of the applicant’s specification).
With respect to claim 5, Volition teaches wherein the degree of agglutination or precipitation is measured by transmittance (see, e.g., para. spanning col. 15-16: “The immunoassays of the invention include immunometric assays employing […] immunoturbidimetric assays”). The applicant’s specification discloses that the immunoturbidimetric assay of Volition meets the limitations of claim 5 (see, the para. spanning p. 5-6 of the applicant’s specification).
With respect to claim 6, Volition teaches wherein the antibody is monoclonal (see, e.g., col. 14, lines 23-25: “The antibody can be a monoclonal antibody or a fragment thereof capable of specific binding to the biomarker”).
With respect to claim 9, Volition teaches wherein the body fluid sample is blood, serum, or plasma (see, e.g., col. 16, lines 9-12: “In one embodiment, said biological sample comprises a body fluid. For example, biological samples that may be tested in a method of the invention include cerebrospinal fluid (CSF), whole blood, blood serum, plasma”).
With respect to claim 10, Volition teaches wherein the blood, serum or plasma sample is obtained from a subject suffering, or suspected to be suffering, from sepsis (see, e.g., col. 15, lines53-59: “It will be clear to those skilled in the art that the invention will have application in a variety of disease areas where circulating nucleosomes have been found in subjects. These include, without limitation, trauma (for example; severe injury or surgery), extreme exercise (for example running a marathon), stroke and heart attack, sepsis or other serious infection and endometriosis”).
With respect to claim 12, Volition teaches wherein the ETs comprise neutrophil extracellular traps (NETs) (see, e.g., col. 6, lines 13-25: “According to a second aspect of the invention there is provided a method for detecting nucleosomes in a sample which comprises the steps of: (i) contacting the sample with a first binding agent which binds to nucleosomes; (ii) contacting the nucleosomes or sample with two or more second binding agents which bind to different or separate nucleosome epitopes; (iii) detecting or quantifying the binding of said multiple second binding agents to nucleosomes in the sample; and (iv) using the presence or degree of such binding as a measure of the presence of nucleosomes in the sample”, and col. 5, lines 53-56: “We now report simple immunoassay methods for the direct estimation of nucleosome associated 5-methyl cytosine and 5-hydroxymethyl cytosine DNA methylation in biological samples without extraction”, and para. spanning col. 15-16: “The immunoassays of the invention include immunometric assays employing […] immunoturbidimetric assays”). The applicant’s specification discloses that assays for NETs include nucleosomes, a component of NETs (see, p. 1, last para. of the applicant’s specification).
With respect to claim 13, Volition teaches wherein the nucleosome comprises an epigenetic feature of a cell free nucleosome and the one or more antibodies are capable of specific binding to the epigenetic feature of the cell free nucleosome (see, e.g., col. 3, lines 34-35: “Histone variants (also known as histone isoforms) are also known to be epigenetic regulators of gene expression”, and col. 14, lines 7-10: “According to a further aspect of the invention there is provided a kit for detecting or measuring nucleosomes containing two or more epitopes including a histone variant or histone PTM”).
With respect to claim 14, Volition teaches wherein the epigenetic feature is a histone isoform or a histone post translational modification (PTM) (see, e.g., para. spanning col. 13-14: “According to another aspect of the invention there is provided a kit for detecting or measuring nucleosomes which comprises multiple capture and/or detection ligands or binders specific for a nucleotide or histone variant or histone PTM or a component part thereof”).
With respect to claim 15, Volition teaches wherein the histone PTM is a histone PTM
of a core nucleosome (see, e.g., col. 11, lines 4-5: “We measured nucleosomes containing the three histone variants, as well as the histone PTM P-H2AX(Ser139)”). The applicant’s specification discloses, “The histone PTM may be a histone PTM of a core nucleosome, e.g. H3, H2A” (see, p. 10, para. 1).
With respect to claim 16, Volition teaches wherein the histone isoform is a histone H3 isoform (see, e.g., col. 2, lines 19-24: “These assays typically employ a monoclonal anti-histone antibody (for example anti-H2B, anti-H3 or anti-H1, H2A, H2B, H3 and H4) as capture antibody and a monoclonal anti-DNA or anti-H2A-H2B-DNA complex antibody as detection antibody”).
With respect to claim 19, Volition teaches a method of monitoring the progress of a disease in a subject, comprising:
(i) detecting a concentration of nucleosomes in a body fluid sample obtained from a subject using the method of claim 1 (see above)
(ii) repeating step (i) on one or more occasions; and
(iii) using any changes in the concentration of nucleosomes to monitor the progression of the disease in the subject (see, e.g., col. 15, lines 23-27: “Methods of detecting, monitoring and of diagnosis according to the invention are useful to confirm the existence of a disease, to monitor development of the disease by assessing onset and progression, or to assess amelioration or regression of the disease”, and col. 16, lines 21-28: “the method of the invention is repeated on multiple occasions. This embodiment provides the advantage of allowing the detection results to be monitored over a time period. Such an arrangement will provide the benefit of monitoring or assessing the efficacy of treatment of a disease state. Such monitoring methods of the invention can be used to monitor onset, progression, stabilisation, amelioration, relapse and/or remission”).
With respect to claim 20, Volition teaches a method of assigning a risk of an adverse outcome to a subject suffering from an infection, comprising:
(i) detecting a concentration of ETs, chromatin fragments and/or nucleosomes in a
body fluid sample obtained from a subject using the method of claim 1; and
(ii) using the concentration of ETs, chromatin fragments and/or nucleosomes detected to assign the likelihood of an adverse outcome to said subject, wherein a subject identified with a high likelihood of an adverse outcome is assigned for medical intervention (see, e.g., col. 7, lines 30-37: “According to a further aspect of the invention there is provided a method for assessment of an animal or a human subject for suitability for a medical treatment which comprises the steps of: (i) detecting or measuring nucleosomes in a body fluid of a subject according to a method of the invention; and (ii) using the nucleosome level detected as a parameter for selection of a suitable treatment for the subject”, and claim 14 of Volition: “A method for assessment of an animal or a human subject for suitability for a medical treatment which comprises the steps of: (i) detecting or measuring nucleosomes in a body fluid of a subject according to the method of claim 1; and (ii) using the nucleosome level detected as a parameter for selection of a suitable treatment for the subject”).
With respect to claim 27, Volition teaches a method of detecting a subject in need of medical treatment for sepsis or septic shock, comprising:
(i) detecting a concentration of ETs and/or chromatin fragments and/or nucleosomes in a body fluid sample obtained from the subject using the method of claim 1; and
(ii) using the concentration of ETs and/or chromatin fragments and/or nucleosomes
as an indicator that the subject is in need of medical treatment for sepsis (see, e.g., col. 15, lines 53-62: “It will be clear to those skilled in the art that the invention will have application in a variety of disease areas where circulating nucleosomes have been found in subjects. These include, without limitation, trauma (for example; severe injury or surgery), extreme exercise (for example running a marathon), stroke and heart attack, sepsis or other serious infection and endometriosis. As methods of the current invention are capable of detection of a wider range of nucleosomes than current nucleosome ELISA methods, applications in further disease areas may be found”, and claim 14 of Volition: “A method for assessment of an animal or a human subject for suitability for a medical treatment which comprises the steps of: (i) detecting or measuring nucleosomes in a body fluid of a subject according to the method of claim 1; and (ii) using the nucleosome level detected as a parameter for selection of a suitable treatment for the subject”).
With respect to claim 28, Volition teaches a kit for measuring the concentration of nucleosomes in a body fluid sample comprising: a reagent solution comprising one or more antibodies capable of specific binding to nucleosomes and a container suitable for use in a means to measure the degree of agglutination or precipitation caused upon antibody binding to determine the concentration of nucleosomes (see, e.g., col. 19, lines 21-31: “Diagnostic kits for the diagnosis and monitoring of the presence of a disease state are described herein. In one embodiment, the kits additionally contain a biosensor capable of identifying and/or quantifying a biomarker. Suitably a kit according to the invention may contain one or more components selected from the group: a ligand binder, or ligands, specific for the biomarker or a structural/shape mimic of the biomarker, one or more controls, one or more reagents and one or more consumables; optionally together with instructions for use of the kit in accordance with any of the methods defined herein”).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Micallef, as applied to claims 1-2, 5-6, 8-9, 12-15, 19, and 28 above, and further in view of Price (“Development and validation of a particle-enhanced turbidimetric immunoassay for C-reactive protein”, published 1987).
Micallef teaches as set forth above, but fails to teach wherein the one or more
antibodies are present in a suspension of antibody coated particles, such as latex particles, as in claims 3-4.
However, Price teaches a latex particle-enhanced turbidimetric immunoassay (PETIA), wherein the antibodies are present in a suspension of antibody coated particles, such as latex particles, as in claims 3-4 (see, e.g., p. 205, col. 2, para. 1).
Micallef and Price are analogous to the field of the claimed invention because they are both in the field of immunoturbidimetric assay. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the latex-particle enhancement of Price in the method of Micallef. An artisan would have been motivated to do so because Price discloses, “Immunoturbidimetric methods have a practical detection limit of 10-20 mg/l in the sample but the sensitivity can be increased by enhancing the light scattering properties of the immunoaggregates by attaching latex particles to the antibody” (see, e.g., p. 205, para. spanning col. 1-2). An artisan would have had a reasonable expectation of success based on the given disclosures.
Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Volition, as applied to claims 1-2, 5-6, 8-10, 12-16, 19-20, and 27-28 above, and further in view of Price (cited above).
Volition teaches as set forth above, but fails to teach wherein the one or more
antibodies are present in a suspension of antibody coated particles, such as latex particles, as in claims 3-4.
However, Price teaches a latex particle-enhanced turbidimetric immunoassay (PETIA), wherein the antibodies are present in a suspension of antibody coated particles, such as latex particles, as in claims 3-4 (see, e.g., p. 205, col. 2, para. 1).
Volition and Price are analogous to the field of the claimed invention because they are both in the field of immunoturbidimetric assay. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the latex-particle enhancement of Price in the method of Volition. An artisan would have been motivated to do so because Price discloses, “Immunoturbidimetric methods have a practical detection limit of 10-20 mg/l in the sample but the sensitivity can be increased by enhancing the light scattering properties of the immunoaggregates by attaching latex particles to the antibody” (see, e.g., p. 205, para. spanning col. 1-2). An artisan would have had a reasonable expectation of success based on the given disclosures.
Claims 1-2, 8, and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Kessenbrock (“Netting neutrophils in autoimmune small-vessel vasculitis”, published 2009) in view of Price (cited above).
Kessenbrock teaches a method of detecting extracellular traps (ETs), comprising:
analyzing the body fluid sample using an immunoassay method, and using results obtained from said analyzing to determine a concentration of ETs in the body fluid sample, as in claim 1 (see, e.g., p. 624, under “Figure 2” caption: “Quantification of MPO-DNA complexes in the serum samples. The mean optical density as measured by capture ELISA”). Kessenbrock teaches wherein the immunoassay method comprises: (a) mixing the body fluid sample with a solution of one or more antibodies, wherein said antibodies are capable of specific binding to ETs, as in claim 2 (see, e.g., p. 624, under “Figure 2” caption: “Quantification of MPO-DNA complexes in the serum samples. The mean optical density as measured by capture ELISA”). Kessenbrock teaches wherein the ETs comprise neutrophil ETs and the antibodies are capable of specific binding to a protein associated with a neutrophil extracellular trap (NET), specifically myeloperoxidase (MPO), as in claims 17-18 (see, e.g., p. 624, under “Figure 2” caption: “Quantification of MPO-DNA complexes in the serum samples. The mean optical density as measured by capture ELISA”).
Kessenbrock fails to teach the immunoassay is a homogeneous assay and the antibody binding causes agglutination, as in claims 1-2, 8, and 17-18. However, Price teaches a latex particle-enhanced turbidimetric immunoassay (PETIA), wherein the antibodies are present in a suspension of antibody coated particles, as in claims 1-2, 8, and 17-18 (see, e.g., p. 205, col. 2, para. 1).
Kessenbrock and Price are analogous to the field of the claimed invention because they are both in the field of immunoassays of serum proteins. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the latex-particle enhancement of Price in the method of Kessenbrock. An artisan would have been motivated to do so because Price discloses, “Immunoturbidimetric methods have a practical detection limit of 10-20 mg/l in the sample but the sensitivity can be increased by enhancing the light scattering properties of the immunoaggregates by attaching latex particles to the antibody” (see, e.g., p. 205, para. spanning col. 1-2). Price also discloses, “Turbidimetric techniques are now more widely used because of the applicability of the technique to a wide variety of automated instruments” (see, p. 210, under “Discussion”, para. 1). An artisan would have had a reasonable expectation of success based on the given disclosures.
Conclusion
No claims are allowed.
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/MICHAEL CAMERON SVEIVEN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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