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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 5/3/26 is acknowledged.
Claim Status
The claim set filed 5/3/26 is acknowledged. Claims 11, 19, and 27-30 are cancelled. Claims 1-10, 12-18, and 20-26 are pending. Claims 3-4 and 18 are amended. Claims 1-10, 12-18, and 20-26 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 8 and 26 are objected to because of the following informalities: the claims contain acronyms, abbreviations and/or initialisms that should be spelled out upon first occurrence. Appropriate correction is required.
Claim 26 is objected to because of the following informalities: the claim does not have a period at the end of the claim. See MPEP 608.01(m). Appropriate correction is required.
Claim 26 is objected to because of the following informalities: the phrase “will have or likely to have” should be amended to read “will have or is likely to have”. Appropriate correction is required.
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.
Claims 1-10, 12-18, 20-26 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.
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 “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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.
The instant claims are directed to methods comprising obtaining a biological sample from a subject that is undergoing or has undergone surgery, and detecting brain-derived exosomes in the sample by contacting the sample with antibodies and detecting the binding between the brain derived exosomes and the antibodies. The dependent claims identify antigens that the antibodies may bind, types of exosomes, types of brain damage, and sample types.
The methods are required to perform a specific function without providing adequate description of the steps of the method, or the reagents used in the method.
Regarding the steps of the methods, the claimed methods do not set forth adequate description for identifying exosomes that are “brain-derived,” and have not identified how detecting a brain derived exosomes could measure or detect brain damage. The measured biomarkers and controls needed for identifying the brain damage are not defined, and the exact steps of the method, including thresholds, measurement techniques, types of measurements, or comparisons made, are not adequately described. The method doesn’t even specify whether the measurement would be increased or decreased relative to a control, and in fact, depend claim 15 specifically provides that the measurement can be either increased or decreased. The methods further do not identify any selection steps for treatment, or identify any means for correlating a measurement with any specific type of treatment.
Regarding the reagents used in the methods, the instant claims require antibodies that bind to “brain-derived exosomes” but neither the claims nor the specification adequately define the characteristics of the exosomes other than their origin, the specific target molecules that identify the exosomes as being “brain-derived,” or the specific antibodies that could bind to “brain-derived exosomes.”
The claimed methods require the practitioner to first perform experimentation to identify characteristics of the “brain-derived exosomes” then perform further experimentation to identify the reagents that would bind these exosomes and identify them in the claimed method, then perform experimentation to identify the specific steps of the method that would allow for conclusions to be made regarding status of brain damage. The claimed methods further require experimentation to correlate measurement of exosomes to specific treatments, which have not been identified. The need for experimentation to identify basic steps and components of the method suggests that the method itself has not been adequately described.
For the reasons set forth above, the claimed method does not set forth a specific structure (i.e. method steps and specific reagents) that correlate to the required functions. The instant specification also does not describe a representative number of species for the claimed methods for the breadth for the breadth of the claimed genus. Further, the specification provides no guidance regarding which method steps and reagents are capable of the required functions. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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 detection of exosomes and use for measurement of disease states is highly unpredictable. As stated in MPEP 2163, in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. Ludwig et al (Int. J. Mol. Sci. 2019, 20, 4684) teaches that, although many novel approaches to exosome isolation and analysis of their cargos have been introduced, the role of exosomes as diagnostic or prognostic biomarkers of disease remains unconfirmed (see e.g. abstract). Studies of body fluid-derived exosomes are a challenge, since the isolated exosomes are derived from many different cell types and contain components of body fluids (“contaminants’), which have to be removed during exosome isolation (see e.g. page 2). Recent technological progress in exosome isolation and their analysis has not led to a universally accepted recommendation for exosome isolation (see e.g. page 2). The field is facing problems in selecting and reproducing various isolation methodologies (see e.g. page 2). In the field of exosome research, no gold standard for exosome isolation exists (see e.g. page 2). Although ultracentrifugation is widely used in the field, the technique has several drawbacks, including the co-isolation of non-exosomal impurities, low reproducibility, low RNA yield, potential damage of exosomes and low-throughput of samples, which is not compatible with clinical utilization (see e.g. page 2). Reports in the literature suggest that different isolation methods introduce variations in the concentration, purity and size of exosomes (see e.g. page 3). Isolation of exosomes by direct immunocapture from cell culture supernatants or body fluids might overcome the ”contamination” problem; however, immune capture is strictly dependent on specific binding of the detection antibody to an antigen on the exosome surface (see e.g. page 3). Therefore, the presence of “contaminants” is likely to interfere with immune capture (see e.g. page 3). In aggregate, the “purity” of exosome samples is highly dependent on the vesicle isolation method, and it is likely to affect results interpretation (see e.g. page 3).
Not only exosome isolation methods, but also the nomenclature of EVs remains unclear (see Ludwig, page 2). The recent introduction of exomeres (200 nm), encompassing microvesicles, oncosomes and apoptotic bodies, emphasizes the heterogeneity of exosome vesicles (see e.g. page 2).
He et al (International Journal of Pharmaceutics 689 (2026) 126471) also describe that even as exosome research continues to evolve, maintaining the accuracy, scientific rigor, and standardization of methodologies poses a significant challenge (see e.g. section 2.2). The exosome industry remains predominantly in the pre-clinical research and development phase, largely due to challenges such as the low abundance of proteins and RNA molecules within exosomes, difficulties in their isolation and extraction, the need for large sample volumes, and complex, time-consuming procedures (see e.g. section 3.2). Achieving high purity, stability, and efficiency in obtaining exosomes is difficult, and even when possible is time-consuming and labor-intensive, making isolation of exosomes from clinical samples with common techniques unsuitable for clinical investigation (see e.g. section 2.4).
Furthermore, in addition to the unpredictable nature of isolation and measurement of exosomes and exosome characteristics, the use of exosomes as a biomarker in the instant claimed method is highly unpredictable. The skilled artisan cannot envision the steps, specific assay methods and specific measurement thresholds that are required to establish specific status outcomes. In general, the art regarding establishing biomarkers is unpredictable. Waiker et al (J Am Soc Nephrol. 2012 January; 23(1): 13–21) teach that although diagnostic tests are judged based on their ability to classify individuals according to disease status, the actual disease status is often not known with certainty in clinical medicine. While testing blood biochemical markers is accepted as a marker of disease, few diagnostic tests enjoy acceptance as biomarkers (see page 2). This is particularly a problem when the new test is being compared to an imperfect standard test (see page 1). It is also important to note that Waiker et al discuss the necessity of specific thresholds. The threshold established for any given biomarker to describe any particular disease is critical for establishing the accuracy of the biomarker to predict disease (see page 8).
The measurement of exosomes as biomarkers is particularly unpredictable. Park et al (BioChip Journal (2025) 19:411–423) teaches that despite their promise, the clinical translation of exosome-based diagnostics is hindered by challenges including the low abundance of exosomes and their molecular cargoes, as well as the lack of standardized reference materials for quality control and limitations of conventional detection methods (see e.g. page 413). While techniques such as ELISA may be able to detect exosomal surface proteins, their sensitivity may be insufficient for detecting low-abundance biomarkers in early-stage diseases, especially without well-validated antibodies (see e.g. page 413). Further, Park describes many hurdles must be addressed for clinical and commercial translation of exosomes, including the absence of standardized protocols for exosome isolation and purification, the lack of standardized reference materials for quality control of exosome-based diagnostics, and the relatively low abundance of exosomes in biofluids which necessitates the development of highly sensitive detection technologies (see e.g. page 415).
It is particularly notable that the instant method includes several steps beyond just testing for the biomarker that can introduce variability. These include isolation during a surgical procedure and treatment with a compound, while lacking specific steps for collection, specific markers to identify which exosomes that may be present are “brain-derived” and identification of antibodies that are capable of performing the required functions. In particular, the requirement that one of skill in the art identify an individualized biomarker signature seems to be direction for a practitioner to actually perform experimentation to determine what the claimed method is, without providing guidance about how this would be accomplished. This seems to be expression of merely a wish or plan for the invention, without actually possessing the invention itself. The claimed method does little more than name a genus of “a method” or “a method for measuring and/or detecting brain damage” with arbitrary steps that require the practitioner to perform a large amount of experimentation and optimization to practice any of the genus of methods that are encompassed. There is no clear method with specific steps or combinations of biomarkers that would lead one of skill in the art to reasonably be able to practice the claimed method without need for further written description.
Regarding the encompassed antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies, which could bind to any number of possible molecular targets from the exosomes. The specification discloses two possible target proteins of CD171 and CD9, but does not describe any other target proteins or any possible antibodies that would bind these targets and function within the instant method. Therefore, the antibodies required in the instant method are also inadequately described.
The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Therefore, neither the art nor the specification provide a sufficient representative number of method steps or reagents such as antibodies used in the instant method, or a sufficient structure-function correlation to meet the written description requirements.
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
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 1-10, 12-18, 20-26 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.
Claims 1, 2, 5, 15, 21-22, and 25 recite “brain-derived exosomes.” However, the specification does not provide means for identification of such exosomes. It is unclear what characteristics must be present for an exosome to be considered “brain-derived.” Without clearly identifying those characteristics, the claimed invention is indefinite.
Claim 1 recites “contacting the sample with antibodies” but then claim 2 recites “with a second antibody” and claim 3 recites “wherein the antibodies are anti-CD171 antibodies”. It is therefore unclear what antibodies are required by the term “antibodies”. The term could encompass multiple molecules of the same antibody, multiple different antibodies, or multiple molecules of multiple different antibodies.
Claim 2 and 4 recites the limitation "second antibody". There is insufficient antecedent basis for this limitation in the claim. In particular, claim 1 recites multiple “antibodies” and therefore it is unclear how “the second antibody” is distinguished from the multiple antibodies in claim 1.
Claim 3 recites “wherein the antibodies are anti-CD171 antibodies”. It is unclear if the claim requires multiple molecules of the same anti-CD171 antibody, or if the claim is requiring multiple different anti-CD171 antibodies that bind to different antigens.
Claims 6, 7, and 23 recite “neuron-derived exosomes, astrocyte-derived exosomes, oligodendrocyte-derived exosomes, and microglia- derived exosomes.” However, the specification does not provide means for identification of such exosomes. It is unclear what characteristics must be present for an exosome to be considered “neuron-derived exosomes, astrocyte-derived exosomes, oligodendrocyte-derived exosomes, and microglia- derived exosomes.” Without clearly identifying those characteristics, the claimed invention is indefinite.
In claim 14, the method requires “measuring and/or detecting brain damage in a subject undergoing a surgical procedure”, wherein the measurement can happen “before…undergoing surgery”. It is impossible to determine brain damage from a patient undergoing surgery if the patient is not currently undergoing or has undergone a surgical procedure. In other words, measuring brain damage “before” surgery would not measure brain damage from “undergoing surgery”.
The term “minimize” in claim 16 is a relative term which renders the claim indefinite. The term “minimize” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The term “likely to have” in claim 26 is a relative term which renders the claim indefinite. The term “likely to have” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
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 14-18 and 20-26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements, which are recited at a high level of generality, provide conventional assays and samples that do not add meaningful limits to practicing the law of nature and abstract idea.
The Supreme Court in Mayo laid out a framework for determining whether an applicant is seeking to patent a judicial exception itself, or a patent-eligible application of the judicial exception. See Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. 66, 101 USPQ2d 1961). See MPEP 2106. The first step of the analysis asks whether the claimed invention is directed to a statutory category of invention. The rejected claims recite a method of measuring and/or detecting brain damage in a subject undergoing a surgical procedure, and a method for preventing, minimizing, or treating damage to a brain during surgery, with both methods comprising obtaining a biological sample, detecting whether brain-derived exosome is present by contacting the sample with an antibody and detecting the binding between the brain-derived exosome and the antibody. The method for measuring and/or detecting brain damage also requires comparing levels of brain-derived exosomes, and the method for preventing, minimizing or treating damage to a brain during surgery comprises “administering an effective amount of a compound to prevent, minimize, or treat damage to the brain.” The claims are directed to a method, which is a statutory category of invention.
Second, the claimed invention also must qualify as patent-eligible subject matter, i.e., the claim must not be directed to a judicial exception unless the claim as a whole includes additional limitations amounting to significantly more than the exception (see MPEP 2106). Based upon an analysis with respect to the claim as a whole, the instant claims are determined to be directed to a law of nature/natural principle and an abstract idea. The relationship between the recited biomarkers and presence of brain damage, or a risk of brain damage, is a natural principle, which is a judicial exception. This method describes correlation of a particular biomarker with a particular natural disease state, which is comparable to concepts identified by the Supreme Court in Mayo. (see Mayo 101 USPQ2d at 1966). The use of the biomarkers and correlation with disease could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics, or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams).
Third, a claim that focuses on the use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. See Mayo 101 USPQ2d at 1966. Adding steps to a natural biological process that only recite well-understood, routine, conventional activity previously engaged in by researchers in the field would not be sufficient. See id. At 1966, 1970. The claims identifies sample types (e.g. blood, serum, plasma, etc.) for testing and subjects to be tested, and the specification identifies well-known assays for detecting and/or measuring gene expression products. The identification of sample types and subjects from which the samples are to be collected is routine in the art of medical testing. As stated in MPEP 2106.05(d), the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity. Determining the level of a biomarker in blood by any means has been determined as one of the well-understood, routine, conventional activity: see 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). Regarding the assays to detect protein expression products, the assays claimed are routine in the art for measuring protein expression. This is acknowledged by the instant specification, which states that "The practice of the present disclosure will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, cell biology, genetics, immunology and pharmacology, within the skill of the art.” (see paragraph [0030]). Therefore, the additional features of the claims (i.e., measuring the level of the recited biomarkers, and identifying the source of the sample for screening) do not ensure that the claims amount to significantly more than the natural principle itself. The claims use conventional means to observe a natural correlation and therefore the steps of the claimed methods are not sufficient to transform unpatentable natural correlations into patentable applications of those regularities. This is also supported by the findings of the in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 115 USPQ2d 1152 (Fed. Cir. 2015), wherein the Federal Circuit held that claims that measure biological substances using methods that are routine and conventional do not amount to more than reliance on a correlation that is a law of nature for patentability.
The treatment step of instant claim 16 is not sufficiently particular to meet the requirement for additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. As stated in MPEP 2106.04(d)(2), the treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). A claim that recites an abstract idea and "administering a suitable medication to a patient,” which is similar in scope to instant claim 16, is not sufficiently particular. See MPEP 2106.04(d)(2). This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application.
The question of whether identification of the patient population amounts to significantly more than the judicial exception is addressed in Mayo Collaborative Serv. v. Prometheus Labs., Inc., 566 U.S. _, 132 S. Ct. 1289, 1293-94, 101 USPQ2d 1961, 1965-66 (2012) (citing Diehr, 450 U.S. at 187, 209 USPQ at 7), when the Supreme Court determined that process claims reciting a correlation may inhibit further discovery by improperly tying up future use of laws of nature, even though the laws of nature at issue are narrow laws that may have limited applications. After measurement of the correlation, the claims can tie up a doctor's subsequent treatment decisions, whether treatment does or does not change in light of inference the doctor has drawn using disclosed correlations, since the claims threaten to inhibit development of more refined treatment recommendations that combine the patentee's correlations with later discovered features, and since the correlation step of the claims is set forth in highly general language covering all processes that make use of the correlation. Further, the steps simply refer to a relevant patient population, which is a pre-existing audience; doctors wish to determine whether a particular patient has a disease, or if the disease has/has not progressed. The claims inform a relevant audience about certain laws of nature; and additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community, and those steps, when viewed as a whole, add nothing significant beyond the sum of the parts taken separately. Even though the laws of nature at issue are narrow laws that may have limited applications, the claim does not amount to significantly more than the natural law itself.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 1-6, 9, 12, 14-17, 20-24 is/are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(1) as being anticipated by Pawlowski et al (US 2015/0152474 A1; filed 3/11/13; published 6/4/15).
Claim 1 is directed to a method comprising: (i) obtaining a biological sample from a subject that is undergoing or has undergone surgery, and (ii) detecting brain-derived exosomes in the sample by contacting the sample with antibodies and detecting binding between the brain-derived exosomes and the antibodies.
Claim 2 is directed to the method of claim 1, wherein the detecting binding between the brain-derived exosomes and the antibodies further comprises contacting the brain-derived exosomes with a second antibody.
Claim 3 is directed to the method of claim 1, wherein the antibodies are anti- CD171 antibodies, anti-EAAT1 antibodies, or anti-MOG antibodies.
Claim 4 is directed to the method of claim 2, wherein the second antibody is an anti-CD9 antibody, an anti-CD63 antibody, or an anti-CD81 antibody.
Claim 5 is directed to the method of claim 1, further comprising quantifying the levels of brain-derived exosomes in the biological sample.
Claim 6 is directed to the method of claim 1, wherein the exosomes are selected from the group consisting of neuron-derived exosomes, astrocyte-derived exosomes, oligodendrocyte-derived exosomes, and microglia-derived exosomes.
Claim 7 is directed to the method of claim 1, further comprising determining a ratio of two exosomes selected from the group consisting of neuron-derived exosomes, astrocyte-derived exosomes, oligodendrocyte-derived exosomes, and microglia- derived exosomes.
Claim 8 is directed to the method of claim 7, wherein a lower ratio of NDE/ADE and/or ODE/ADE prior to surgery indicates that the subject will have postoperative delirium.
Claim 9 is directed to the method of claim 1, wherein the subject has been diagnosed or is suspected of having brain damage.
Claim 10 is directed to the method of claim 9, wherein the brain damage is postoperative cognitive dysfunction or decline (POCD).
Claim 12 is directed to the method of claim 1, wherein the biological sample is selected from the group consisting of whole blood, serum, plasma, urine, interstitial fluid, peritoneal fluid, cervical swab, tears, saliva, buccal swab, skin, brain tissue, and cerebrospinal fluid.
Claim 13 is directed to the method of claim 1, wherein the surgery is cardiac surgery.
Claim 14 is directed to a method for measuring and/or detecting brain damage in a subject undergoing a surgical procedure comprising: (i) obtaining one or more biological samples from a subject before, during, and/or after undergoing surgery or any combination thereof, (ii) detecting brain-derived exosomes in the one or more samples by contacting the one or more samples with antibodies and detecting binding between the brain-derived exosomes and the antibodies, and (iii) comparing the levels of brain-derived exosomes in the one or more samples to a control.
Claim 15 is directed to the method of claim 14, wherein the levels of brain-derived exosomes are increased or reduced compared to a control.
Claim 16 is directed to a method for preventing, minimizing, or treating damage to a brain during surgery, comprising: (i) obtaining a biological sample from a subject that is undergoing or has undergone surgery, (ii) detecting whether a brain-derived exosome is present in the sample by contacting the sample with an antibody and detecting binding between the brain-derived exosome and the antibody, and (iii) administering an effective amount of a compound to prevent, minimize, or treat damage to the brain.
Claim 17 is directed to the method of claim 16, wherein the biological sample is selected from the group consisting of whole blood, serum, plasma, urine, interstitial fluid, peritoneal fluid, cervical swab, tears, saliva, buccal swab, skin, brain tissue, and cerebrospinal fluid.
Claim 18 is directed to the method of claim 17, wherein the compound is selected from the group consisting of an anti-inflammatory compound, an anti-=oxidative stress compound, a free radical scavenger, and a neuronal growth and survival factor compound.
Claim 20 is directed to the method of claim 16, wherein the compound is administered before, during, or after the surgery.
Claim 21 is directed to the method of claim 16, wherein the compound is administered if brain-derived exosomes are detected in the sample.
Claim 22 is directed to the method of claim 16, wherein the compound is administered if brain-derived exosomes are increased or reduced in the sample compared to a control.
Claim 23 is directed to the method of claim 16, wherein the exosomes are selected from the group consisting of neuron-derived exosomes, astrocyte-derived exosomes, oligodendrocyte-derived exosomes, and microglia-derived exosomes.
Claim 24 is directed to the method of claim 16, wherein the biological sample is selected from the group consisting of whole blood, serum, plasma, urine, interstitial fluid, peritoneal fluid, cervical swab, tears, saliva, buccal swab, skin, brain tissue, and cerebrospinal fluid.
Claim 25 is directed to the method of claim 16, further comprising determining the ratio of at least two brain-derived exosomes in the biological sample.
Claim 26 is directed to the method of claim 25, wherein a lower ratio of NDE/ADE and/or ODE/ADE prior to surgery indicates that the subject will have or likely to have postoperative delirium
R
Regarding the limitations of instant claim 1 and 14, Pawlowski teaches biomarkers for diagnostic, therapy-related or prognostic methods to identify phenotypes such as a condition or disease and select candidate treatment regimens (see e.g. abstract). The method can include assessing one or more vesicles such as exosomes (see e.g. paragraph [0098]). The vesicles may be present in a biological sample (see e.g. paragraph [0098]). The vesicle can have a biosignature that is specific to the cell of origin, and can be used to derive disease specific or biological state specific diagnostic, prognostic or therapy related biosignatures (see e.g. paragraph [0316]). The biosignatures can be used to along with surgery, such as pre-surgery or post-surgery (see e.g. paragraph [0317]). The method can include detecting the presence of one or more microvesicle in a biological sample comprising isolating the vesicle, then contacting with a binding agent that binds to a specific cell surface marker (see e.g. paragraph [0156]). The vesicles can be brain-derived vesicles (see e.g. paragraph [0229]-[0230]). The binding agents can be antibodies or antibody fragments (see e.g. paragraph [0027]). The method can compare the level of the vesicle to a control sample (see e.g. paragraph [0017], Example 41, paragraph [0433] and [1082]).
Regarding the limitations of instant claim 2, the vesicles can be detected a combination of binding agents that are specific to cell of origin (see e.g. paragraph [0233]).
Regarding the limitations of instant claim 3, the vesicles can be detected using an antibody to L1CAM, which is another name for CD171 (see e.g. paragraph [0405] and Table 5)
Regarding the limitations of instant claim 4, the vesicle can be detected with anti-CD9 antibody (see e.g. paragraph [0156] and [0166]).
Regarding the limitations of instant claim 5, the biosignature can be detected quantitatively, including detecting the presence or measuring the level or concentration of the vesicle (see e.g. paragraph [0444]).
Regarding the limitations of instant claim 6 and 23, the exosomes can be from an astrocytoma, which inherently would be derived from astrocytes (see e.g. paragraph [0075]).
Regarding the limitations of instant claim 9, the instant specification does not define the term “brain damage” and therefore the term is given its broadest reasonable interpretation to include any damage to the brain. Cancer is inherently a damage to the brain, therefore, the detection of a brain cancer such as astrocytomas reads on the instant claims (see e.g. paragraph [0075]).
Regarding the limitations of instant claim 12, 17 and 24, the sample can be blood, sera, saliva, and other sample types (see e.g. paragraph [0581]).
Regarding the limitations of instant claim 15 and 22, the vesicles can be increased relative to disease stage or progression (see e.g. paragraph [0246]).
Regarding the limitations of instant claim 16 and 21, the level of vesicles can be used to assess whether a subject is a responder or non-responder and thereby identify and administer appropriate treatment based on expected response (see e.g. paragraph [0351], [0533]-[0534]). This treatment would inherently treat damage to the brain due to treating a disease such as brain cancer. The instant specification does not define the term “brain damage” and therefore the term is given its broadest reasonable interpretation to include any damage to the brain. Cancer is inherently a damage to the brain, therefore, the detection of a brain cancer such as astrocytomas reads on the instant claims (see e.g. paragraph [0075]).
Regarding the limitations of instant claim 20, the biosignatures can be used to along with surgery, such as pre-surgery or post-surgery (see e.g. paragraph [0317]).
Conclusion
No claim is allowed.
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/ANDREA K MCCOLLUM/ Examiner, Art Unit 1674
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