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 of “Group I, claims 1-10” and “COPB2 as the specific marker protein” is acknowledged.
Claims 11-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 4-7 and 9 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim.
Election was made without traverse in the reply filed on April 27, 2026.
Claim Status
Claims 1-19 are pending in the present application. Claims 4-7, 9, and 11-19 are withdrawn as directed to non-elected inventions and species. Claims 1-3, 8, and 10 are under examination.
Priority
The present application, filed on October 24, 2023 is a 371 of PCT/JP2021/036525, filed on October 1, 2021 and claims priority to foreign application: JAPAN 2020-168107, filed on October 2, 2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
It is noted that no English language translation of the foreign priority document has been filed in this application
Drawings
The drawings are objected to because each of the figures in the supplemental drawings comprise a non-English language character in the upper left hand corner. Furthermore, pages 10-11 of the supplemental drawings are not provided in English.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 51 and 52. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 1-3, 6, and 8-10 are objected to because of the following informalities:
The phrase “…a COVID-19 patient develops severe symptom…” appears to omit either the article “a” prior to “severe symptom” (singular) or omits a terminal “s” at the end of “symptom” (plural). Claims 2-3, 6, and 8-10 recite similar apparent syntax errors.
Appropriate correction is required.
Claim Interpretation
Special definitions:
Level: “the level means an index related to an abundance converted into a numeric value” (specification paragraph 0055)
Severe symptom: “development of severe symptom means score 5 or greater (hospitalized-severe disease in the following WHO 2020 scoring for COVID-19 cases” (specification paragraphs 0011-0012)
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Exosome: “exosomes refers to an extracellular vesicle of approximately 20 to 200 nm or 50 to 150 nm in diameter that is released from various cells, and is also referred to as EV.” (specification, paragraph 0013)
“control protein level”: “means a marker protein level to be compared… “to be compared means a marker protein level in exosomes in blood from a healthy person or… in a non-severe… COVID-19 patient” (specification, paragraph 0022)
Claim Rejections - 35 USC § 112(a)- Written Description
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.
Claim 10 is rejected under 35 U.S.C. 112(a) 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 had possession of the claimed invention.
Relevant to the lack of particular structural limitations in the rejected claims broadly drawn to “subjecting a patient determined to be likely to develop severe symptom to control or treatment against the development of severe symptom”,
MPEP 2163 states:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
Additionally, at 2163IIA3(a), the MPEP states:
“…describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene “because it is only an indication of what the gene does, rather than what it is.”); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
Claim 10 is broadly drawn to: methods for determining a likelihood that a COVID-19 patient develops severe symptoms, comprising: measuring a level of a marker protein (COPB2) present in exosomes in blood derived from the patient, comparing the measured level with a control protein level (i.e. a level of COPB2 in blood exosomes in a healthy control or mild COVID-19 case)… and subjecting a patient determined to be likely to develop severe symptoms to control or treatment against the development of severe symptoms.
In the instant case, the functionality of “treatment against the development of severe symptoms” (i.e. prevention of symptom progression to the defined “severe” category) is a critical feature of the claimed methods.
The specification teaches “subjecting COVID-19 patient determined to be likely… to prophylactic procedures against the development of severe symptom. Examples… can include administration of vaccines, therapeutic drugs, or prophylactic drugs, treatment or procedures with ventilators, ECMO, or IMPELLA, and elevated frequencies of monitoring of patients’ symptoms” (specification, paragraph 0060). However, the specification does not teach any particular examples of vaccines, therapeutic drugs, or prophylactic drugs.
While the skilled artisan may be capable of developing, screening for, or discovering “vaccines, therapeutic drugs, or prophylactic drugs” with the claimed function “treatment against the development of severe disease”, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
The claims encompass a genus of structurally undefined compounds which require a specific functionality. However, the specification fails to teach how to distinguish members of the claimed genus of compounds which possess the claimed functionality: treatment against the development of severe symptom[s] of COVID-19] from non-members.
In analysis of the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, and particularly for claims drawn to a genus, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615.
Further, 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 do 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 USPQ2d at 1966.
Thus, considering the breadth of the “treatments” required by the claimed methods, their specific required functionalities, and the teachings of the instant specification, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter.
Improper Markush Rejection
Claims 1-3, 8, and 10 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Regarding claims 1-3, 8, and 10, the Markush group in question is any alternatively recited combination comprising one or more of the structurally and functionally different biomarkers in claims 1-3, 8, and 10.
Regarding “single structural similarity”, the MPEP at 2117 IIA states that a recognized physical, chemical, or an art recognized class is a class where there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. It is specifically stated that “Thus a Markush grouping is ordinarily proper if all the members for the group belong to a recognized class (whether physical, chemical, or art recognized) and are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed invention, and it is clear from their very nature or from the prior art that all members possess this property”. Therefore, in analysis of whether a claim contains an improper Markush grouping, the MPEP states: A Markush claim contains an “improper Markush grouping” if either (emphasis added): (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use.”
In the instant case, the recited proteins do not share any common structural element that is essential to the asserted utility of being associated with a likelihood that a COVID-19 patient will develop severe symptoms. The different proteins are encoded by different genes located on different chromosomes in the human genome, and are composed of drastically different amino acid sequences with different functions. Furthermore, the prior art does not teach, nor is it clear from their nature, that all of the functionally different biomarkers possess the property of being differentially abundant in exosomes in blood from COVID-19 patients who will progress to severe disease relative to those who will not progress to severe disease.
For example:
The elected protein biomarker, COPB2 is a “coatomer subunit” that helps form the COPI vesicle coat and is a structural element of the non-clathrin vesicular coat complex required for Golgi budding and vesicular trafficking.
KRAS is a small GTPase protein that functions as a central regulator of the RAS cell signaling pathway driving cell proliferation and oncogenesis when activated. This protein is present in the cytosol, cytoplasm, and at the plasma membrane.
PRKCB is protein kinase C beta, a calcium- and diacylglycerol- dependent serine/threonine kinase involved in diverse cellular signaling pathways regulating, for example, IKK activation and ferroptosis. This protein is present in the cytoplasm, nucleus, plasma membrane, and nucleoplasm.
RHOC is Rho-related GTP-binding protein, a small GTPase that promotes actin cytoskeleton reorganization and regulates cell shape, attachment, and motility. This protein is present in the cytoplasm and plasma membrane.
CD147 is “basigin”, a transmembrane immunoglobulin superfamily protein that acts at the cell surface to regulate cellular metabolism, angiogenesis, and pathogen invasion. CD147 is further known to function in spermatogenesis, embryo implantation, neural development, and tumor progression. This protein is present in the ER membrane, endosome, plasma membrane, and basolateral plasma membrane.
MFAP4 is microfibril-associated protein 4, a secreted extracellular matrix protein that binds collagen and carbohydrates and is associated with cell adhesion and intercellular interactions. MFAP4 is present in the extracellular space, microfibrils, and elastic fibers and is known to be expressed in the respiratory system, skin, and sperm-producing reproductive system.
CRP is C-Reactive Protein, a component of the innate immune response that is abundant in acute-phase circulation. CRP is known to recognize foreign and damaged plasma membranes and participate in complement activation through its calcium-dependent binding to its ligands. CRP is a known marker of increased severity of COVID-19.
CAPN2 is calpain-2, a calcium-activated, intracellular cysteine protease that is present in the cytosol, plasma membrane, membrane raft, and endoplasmic reticulum.
ADH1B is an alcohol dehydrogenase enzyme that is known to function in the cytosol to metabolize retinol, aliphatic alcohols, hydroxysteroids, and lipid peroxidation products.
Therefore, it is clear that when considering the different protein biomarkers, even in different combinations of protein biomarkers, recited in the alternative in the rejected claims, there does not appear to be any common structure related to the function of the protein biomarkers individually, or any particular combination of protein biomarkers, let alone in association with COVID-19 prognosis.
Furthermore, the alternatively recited protein biomarkers in the groups set forth here do not share a single structural similarity, as each method relies on detection of different “measured levels” of single biomarkers or different combinations of biomarkers. The only structural similarity present is that all the biomarkers are made up of amino acids (i.e. they are all proteins). However, comprising amino acids does not support a conclusion that they have a common single structural similarity because the structure of comprising amino acids alone is not essential to the common activity of having a measured level that is correlated with the likelihood of a patient developing severe symptoms of COVID-19.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
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.
Claims 1-3, 8, and 10 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-3, 8, and 10 are indefinite because it is unclear how the preamble is intended to breathe life and meaning into the claim. The preamble of claim 1 is directed to “A method for determining a likelihood that a COVID-19 patient develops severe symptom”. However, the claims only require a step of: “measuring a level of… protein present in exosomes in blood…” and “comparing the measured level… with a control protein level to determine the likelihood…” (claims 1-3); “further… determining or measuring… age, smoking index, a CRP value in blood, and an ALT value in blood… wherein the likelihood… is determined by using the age, smoking index, CRP value, and/or ALT in combination with the marker protein level” (claim 8); and “subjecting a patient… to control or treatment” (claim 10). Thus, it is not clear if applicant intends to cover any method for determining the level of COPB2 in exosomes in blood derived from a patient and comparing the measured level to a control level, or if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If the claim requires something more, it is unclear what additional active process step the method requires and it appears that the claims are incomplete. The claims fail to positively recite any active process steps that clearly accomplish the goal set forth in the preamble (i.e. “determining a likelihood…”).
Claim 6 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Regarding the non-elected marker RNA species recited by claim 6, the recitation of “marker RNAs” AL732437.2 and AL365184.1 are indefinite because they identify an RNA by Genbank accession numbers that do not correspond with the sequences of the RNAs provided in the specification. Paragraph 0014 of the specification states that the marker RNA is selected from the group (recited in claim 6) and may have, but is not limited to the nucleic acid sequence… seq 1-10 in order…”. The specification provides that AL732437.2 may have, but is not limited to the sequence of SEQ ID NO: 3 and AL365184.1 may have, but is not limited to the sequence of SEQ ID NO: 6. SEQ ID NO: 3 has a length of 2357 nucleotides. SEQ ID NO: 6 has a length of 1689 nucleotides. However, the Genbank records AL732437.2 and AL365184.1 are “unfinished” (i.e. not fully assembled) sequences of sequencing clones from Chromosome 10 having a length of 179976 base pairs and Chromosome 1 having a length of 160195 base pairs, respectively. It is not clear whether the recited marker RNAs, identified in the claims by Genbank accession numbers, and which “may have, but [are] not limited to, the nucleic acid sequences as set forth in… SEQ ID NO 3 and 6” (specification, paragraph 0014) are meant to encompass any one of the following alternative interpretations: consisting of the sequence SEQ ID NO 3, comprising the sequence SEQ ID NO 3, comprising any fragment of the 179976 base pair sequence AL732437.2, consisting of any fragment of the 179976 base pair sequence AL732437.2, comprising the entirety of the 179976 base pair sequence AL732437.2, consisting of the entirety of the 179976 base pair sequence AL732437.2, or something else altogether.
Claim 8 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 8 requires “the likelihood of developing severe symptom is determined by using the age, the smoking index, the CRP value in blood, and/or the ALT value in blood of the patient in combination with the marker protein level… wherein the patient is determined to be likely to develop severe symptom when all of the age, the smoking index, the CRP, and the ALT have a higher numeric value than that of a control which is a healthy person or a mild case.”
This claim language renders the claim indefinite because claim 8 requires that the determination of likelihood of severe disease is completed using a set of factors including the marker protein level: “determining the likelihood… by using… age, smoking index, CRP, and/or ALT in combination with the marker protein level” and further recites that the determination of likelihood of severe disease is completed using all of a set of factors not including the marker protein level “wherein the patient is determined to be more likely… when all of… age, smoking index, CRP, and/or ALT [are] higher… than… a control”.
As such, it is unclear whether the “[determining] the likelihood…” step requires the marker protein level.
Claim 10 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 10 requires: “subjecting a patient determined to be likely to develop severe symptom to control or treatment against the development of severe symptom”.
It is noted that the claim consists of a contingent limitation: “subjecting a patient determined to be likely…” and therefore does not require the performing the “subjecting” step in all embodiments of the invention as presently claimed.
Furthermore, the claim language requires “subjecting a patient… to control or treatment against the development of severe symptom”. “subjecting a patient to control” is not defined by the specification. Given its plain meaning, this claim limitation appears not to positively recite any particular method step, but rather encompasses “doing nothing”.
Additionally, “subjecting a patient… to treatment against the development of severe symptom” is indefinite because it is unclear what particular treatments are to be administered to the patient that is “determined to be likely to develop severe symptom”. The specification provides only: “subjecting COVID-19 patient determined to be likely… to prophylactic procedures against the development of severe symptom. Examples… can include administration of vaccines, therapeutic drugs, or prophylactic drugs, treatment or procedures with ventilators, ECMO, or IMPELLA, and elevated frequencies of monitoring of patients’ symptoms”. It is not clear what “vaccines” or “prophylactic drugs” or “therapeutic drugs” were known in the art at the time of filing (October 2, 2020), as the first COVID-19 trial results were published in November of 2020. Furthermore, the prior art appears to comprise few effective antivirals for use against COVID-19, as apparently the only antiviral with emergency use authorization prior to the filing date of the claimed invention, remdesivir, did not have clear evidence of efficacy against COVID-19 (Sun, “Remdesivir for Treatment of COVID-19: Combination of Pulmonary and IV Administration May Offer Additional Benefit” AAPS J. 2020 May 26;22(4):77 (May 26 2020).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 8, and 10 are rejected under 35 U.S.C 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. 101 requires that to be patent eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. See MPEP 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63,67 (1972); see also MPEP 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Step 2A Prong I
The claims are taken to be directed to a natural phenomenon and an abstract idea.
Claim 1 is directed to “a method for determining a likelihood that a COVID-19 patient develops severe symptom, comprising: measuring a level of one or more types of marker protein present in exosomes in blood derived from the patient; and comparing the measured level of the marker protein with a control protein level to determine the likelihood that the patient develops severe symptom…”
Claim 2 recites particular associations between a level of a marker protein chosen from one of a several subsets of the recited marker proteins relative to the level of the marker protein in a healthy person or in a mildly symptomatic patient and the likelihood of developing severe symptoms.
Claim 3 recites that the control protein level of claim 1 is “a level of the marker protein in a blood sample obtained from a healthy person or a COVID-19 patient who did not develop severe symptom early after infection.”
Claims 1-3 are directed to processes that involves the judicial exception of a law of nature/natural phenomenon (i.e. the natural correlation between the amount of a protein or proteins in exosomes in a COVID-19 patient’s blood and the likelihood that the patient will develop severe symptoms of COVID-19) and an abstract idea (i.e. comparing the measured level to a control).
Claim 8 requires further measuring one or more of: patient age, smoking index, CRP value in blood, and/or the ALT value in blood to determine the likelihood of development of severe COVID-19 symptoms.
Claim 8 further recites additional natural correlations between the likelihood of developing severe symptoms and the age of a patient, a “smoking index”, CRP value in blood, and/or the ALT value in blood (i.e. age, smoking history, amount of C-Reactive Protein in blood, and/or the amount of the liver enzyme alanine aminotransferase in blood).
Claim 10 requires “subjecting a patient determined to be likely to develop severe symptom to control or treatment against the development of severe disease”.
It is noted that as presently recited, claim 10 only requires subjecting the patient to a control or treatment if they are determined to be likely to develop severe symptoms (i.e. the claim does not require that the user do anything if the correlation is not present). Furthermore, in embodiments where the correlation is present, the claim requires subjecting the patient to a control or treatment. A “control” encompasses doing nothing in light of the correlation. Therefore, the claim as presently recited does not require subjecting any patient to any treatment.
A comparison to a control is an abstract idea. (See MPEP 2106.04(a)(2)(III)(A); claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014)
A correlation that preexists in the human is an unpatentable phenomenon. The association between the level or amount of a marker protein and the likelihood that a patient will develop severe COVID-19 symptoms is a law of nature/natural phenomenon.
The “determine the likelihood…” steps recited by claims 1, 2, and 8, amount to no more than a mental step. These steps amount to no more than an “instruction to apply the natural law”. Even if the step requires something more such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the natural law to a new and useful end.
Furthermore, the “subjecting a patient determined to be likely… to control or treatment…” step, recited by claim 10, is a contingent limitation not required by all embodiments of the claim (i.e. if the patient is not determined to be likely…) and further do not require the process user to do anything in light of the natural correlation (subjecting a patient to control or treatment). Therefore, these steps fail to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
Step 2A Prong II
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception. While the claims recite “measuring a level of one or more types of marker protein present in exosomes in blood derived from the patient”, this is not an integration of the exception into a practical application. Rather, this element is data gathering required to perform the method. While claim 10 recites, “further subjecting a patient determined to be likely to develop severe symptom to control or treatment against the development of severe symptom”, this does not require that the user do anything in light of the correlation, much less administer any particular therapy based on the correlation observed by the method. Therefore, the treatment step recited by claim 10 does not integrate the exception into a particular treatment. Rather, this step is equivalent to mere instructions to “apply” the judicial exception because it recites only the idea of a solution “subjecting a patient… to… treatment against the development of severe symptom”, with no restriction on how the result is to be accomplished or what treatments would have been efficacious against the development of severe disease beyond the general instruction to subject patients satisfying a conditional to either control (no treatment) or treatment.
Step 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non-patent eligible elements, are sufficient to “transform the nature of the claims into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. St. at 1297).
The claims are not sufficiently defined as to provide a method which is significantly more than a statement of a natural principle for at least these reasons:
The claims do not add a specific limitation other than what is well-understood, routine, and conventional in the field. Steps directed to “measuring a level of one or more types of marker protein present in exosomes in blood derived from the patient” are mere data gathering steps that amount to extra-solution activity to the judicial exception. The “measuring a level” step tells users to measure the abundance of the recited protein(s) in exosomes in blood by any method. Determining the amount or level of proteins, including several of the recited “marker proteins” in exosomes in blood was well known in the art at the time the invention was made. The prior art, for example, Zaid et al., “Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19” Circulation Research. 2020; 127:1404-1418 (originally published 17 September 2020), teach the quantity of extracellular vesicles (comprising exosomes) in blood from COVID-19 patients is correlated with the severity of COVID-19 symptoms, wherein patients with non-severe symptoms have a larger quantity of extracellular vesicles in blood than either healthy controls or patients with severe COVID-19 symptoms (Zaid et al., figure 4, see below).
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Furthermore, Palviainen et al., “Extracellular vesicles from human plasma and serum are carriers of extravesicular cargo- Implications for biomarker discovery” PLoS ONE15(8):e0236439 (August 19, 2020) and Karimi et al., “Detailed analysis of the plasma extracellular vesicle proteome after separation from lipoproteins” Cellular and Molecular Life Sciences (2018) 75:2873-2886 teach methods for measuring the level of various proteins in exosomes derived from blood, wherein at least the following proteins are known to be present in exosomes in human blood: PRKCB, CD147, ECM1, FGG, CLDN3, CRP, UQCRC2, FGA, FGB, LBP, ORM1, ANGPT1, APOB, GNAZ, ICAM2, PACSIN2, YWHAB, COL6A3, DSC1, EIF4A1, FN1, GNAI2, GNB1, GNA13, ITGA2B, ITGB1, ILK, F11R, LIMS1, NID1, PPIA, PPBP, PECAM1, GP1BB, RAB5B, RALB, CCT2, and ZYX.
The claims do not require the use of any particular non-conventional reagents. Claim 1 recites “measuring a level” with no additional methodological limitations as to what technique(s) are employed to accomplish this step. Therefore, the claim encompasses any method capable of measuring the amount of “marker proteins” present in exosomes in blood derived from the patient.
The courts have recognized the following laboratory techniques as well-understood, routine, and conventional activities in the life science arts when claimed in a merely generic manner or as insignificant extra-solution activity:
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Additionally, the generically recited “subjecting a patient… to… treatment against the development of severe symptom” step (which is not required by the claim as presently recited), merely indicate a field of use in which to apply the judicial exception because limiting drug administration to a population having a likelihood of developing severe COVID-19 symptoms does no more than simply refer to the relevant pre-existing audience of doctors who used symptom monitoring, ventilator treatments, and drugs for managing symptoms to treat patients hospitalized with COVID-19 symptoms.
Examples of limitations that the courts have described as merely indicating a field of use or technological environment in which to apply a judicial exception include:
i. A step of administering a drug providing 6-thioguanine to patients with an immune-mediated gastrointestinal disorder, because limiting drug administration to this patient population did no more than simply refer to the relevant pre-existing audience of doctors who used thiopurine drugs to treat patients suffering from autoimmune disorders, Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 78, 101 USPQ2d 1961, 1968 (2012).
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
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.
Claim(s) 1-3, 8, and 10 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Fujita et al., “Early prediction of COVID-19 severity using extracellular vesicle COPB2”. J Extracell Vesicles 2021 June; 10(8)e12092 (published June 2, 2021).
It is noted that the publication date of the Fujita reference is between the filing date of the Foreign priority document JAPAN 2020-168107 and the filing date of the PCT document PCT/JP2021/036525.
It is noted that the authorship of the Fujita reference is distinct from the inventorship of the instant application because Fujita et al. names additional authors who are not named as inventors in the present application.
This rejection may be overcome by:
The filing of a 132 Katz-type declaration or a declaration under 37 CFR 1.130(a) (see In re Katz, 687 F.2d 450, 455, 215 USPQ 14, 18 (CCPA 1982) and MPEP 717.01(a)(1)(b) “Where the authorship of the prior art disclosure includes the inventor or a joint inventor named in the application, an “unequivocal” statement from the inventor or a joint inventor that he/she (or some specific combination of named joint inventors) invented the subject matter of the disclosure, accompanied by a reasonable explanation of the presence of additional authors, may be acceptable in the absence of evidence to the contrary.
or
providing an English language translation of the certified copy of the foreign priority application in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Regarding claims 1 and 3, Fujita et al. teach measuring levels of marker proteins in extracellular vesicles in blood derived from COVID-19 patients with mild symptoms on admission to hospital and comparing said levels to control levels in uninfected patients with mild symptoms or in healthy controls, wherein the marker proteins comprise COPB2 (Fujita et al., figure 1, see below).
Regarding claim 2, Fujita et al. teach the level of COPB2 protein in blood exosomes is elevated in mild COVID-19 cases that do not progress to severe symptoms (i.e. “group 1” in the figure below) relative to uninfected controls and in cases that do progress to severe symptoms (i.e. “group 2” in the figure below).
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Regarding claim 8, Fujita et al. further teach assessing the following clinical factors in addition to the marker protein(s) above for determining the likelihood of developing severe symptoms: Smoking index, age, CRP value, and ALT value (Fujita et al., Figure 3), wherein values of smoking index, age, CRP, and ALT relative to controls are positively correlated with severe symptoms (Fujita et al., Figure 3).
Regarding claim 10, Fujita et al. teach all patients were admitted to hospital for treatment of COVID-19 symptoms (Fujita et al., page 3, paragraph 1).
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.
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 1-3, 8 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Zaid et al., “Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19” Circulation Research. 2020; 127:1404-1418 (originally published 17 September 2020) in view of Palviainen et al., “Extracellular vesicles from human plasma and serum are carriers of extravesicular cargo- Implications for biomarker discovery” PLoS ONE15(8):e0236439 (August 19, 2020) and Rodriguez-Suarez et al., “Quantitative proteomic analysis of hepatocyte-secreted extracellular vesicles reveals candidate markers for liver toxicity” J. Proteomics 2014 April 18; 103:227-240.
Regarding claims 1-3, Zaid et al., teach the quantity of extracellular vesicles (comprising exosomes) in blood from COVID-19 patients is correlated with the severity of COVID-19 symptoms, wherein patients with non-severe symptoms have a larger quantity of extracellular vesicles in blood than either healthy controls or patients with severe COVID-19 symptoms (Zaid et al., figure 4, see below).
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Furthermore, Palviainen et al., teach: “Biomarkers are sought as measurable indicators of pathological processes and for treatment monitoring. Extracellular vesicles (EVs) contain a rich and multifaceted cargo of proteins, metabolites, lipids and nucleic acids for biomarker discovery, and therefore EVs are an excellent source of potential biomarkers. Although EVs can be isolated from all body fluids and from tissues, blood provides the richest source of EVs. Blood-borne EVs are a heterogeneous population originating from blood cells, endothelial cells, and for example in cancer patients from tumor cells. Therefore, blood EVs may well serve as biomarkers of multiple diseases, either by their concentration or by a selection of molecules derived from their biochemical composition. (Palviainen et al., page 1-2 bridging paragraph).
Finally, Rodriguez-Suarez et al. teach COPB2 protein abundance in extracellular vesicles released from liver cells subjected to external injury (treatment with pro-inflammatory pathogen associated molecular pattern molecules galN or LPS) is associated with response to external injury of liver cells (Rodriguez-Suarez et al., page 232, column 2- page 233, column 1).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the methods taught by Zaid et al. comprising measuring the differential abundance of extracellular vesicles (i.e. exosomes) in blood between healthy individuals, COVID-19 patients with mild symptoms, and COVID-19 patients with severe symptoms to further comprise measuring the abundance of particular biomarker proteins in said extracellular vesicles by the methods taught by Palviainen et al. and Rodriguez-Suarez et al. including extra-vesicular COPB2 in, which Rodriguez-Suarez et al. teach is a marker of hepatocyte (liver cell) injury.
The ordinary artisan would have been motivated to modify the methods of Zaid et al. with the teachings comprising measuring protein abundance in extracellular vesicles (i.e. exosomes) in disease states relative to control taught by Palviainen et al. and Rodriguez-Suarez et al. by the teaching of Palviainen et al. that extracellular vesicles in blood are an excellent source of biomarkers of disease and the teaching of Rodriguez-Suarez et al. that COPB2 is present in extracellular vesicles secreted by liver cells in response to pathogen associated molecular pattern molecules GalN and LPS.
Regarding claim 8, Zaid et al. teach measuring one or more of the following factors in combination with the abundance of said extracellular vesicles in blood and determining the association of the factors with severe COVID-19 symptoms: ALT value in blood, CRP value in blood, age, and smoking status (Zaid et al., table 1 and supplement table 1).
Regarding claim 10, Zaid et al. teach COVID-19 patients were admitted to hospital for treatment of symptoms.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Skevaki et al., “Laboratory characteristics of patients infected with the novel SARS-CoV-2 virus” Journal of Infection 81 (2020) 205-212 (published June 21, 2020).
Yang et al., “The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis” Journal of Infection 81 (2020) e13-e20 (published April 10, 2020).
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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