DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Applicant's election with traverse of Group I (claims 1-5; drawn to a method of determining COVID-19 severity) and the claims of Group III (claims 16-19 and 22; drawn to a kit comprising antibodies) in the reply filed on February 9, 2026 is acknowledged. The traversal is on the ground(s) that Applicant’s amendments to independent claim 16 (i.e., making claim 16 depend from claim 1) renders Groups I and III related. This is not found persuasive that the restriction requirement between Groups I and III should be withdrawn because: the inventions of Groups I and III remain patentably distinct.
The inventions of Groups I and III are instantly related as a process and an apparatus for its practice. The inventions are distinct if it can be shown that either: (1) the process as claimed can be practiced by another materially different apparatus or by hand, or (2) the apparatus as claimed can be used to practice another materially different process. See MPEP § 806.05(e). In this case, the process as claimed can be practiced by another materially different apparatus, e.g., colorimetric or fluorometric assays to measure Myeloperoxidase (MPO) activity without antibodies.
Since the inventions of Groups I and III are patentably distinct, the requirement is still deemed proper and is therefore made FINAL.
Claims 6-24 are therefore withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Accordingly, claims 1-24 are presently pending and claims 1-5 are presently under examination; claims 6-24 are presently withdrawn.
Information Disclosure Statement
3. 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.
Objection to the Specification
4. The instant specification is objected to for the following reasons:
a. There are trademarks in this application that do not meet the requirements.
The use of the term (e.g., “KEGG” at para. [0063]), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Please, review the specification for other improper trademarks and correction is required.
b. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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.
c. There are references in this specification that should be placed on an information disclosure statement if application would like them considered.
There are also what appears to be claims under an additional embodiment section; if they are claims they should be placed on a separate page.
Claim Rejections - 35 USC § 112
5. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
6. Claims 1-4 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the 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.
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.)
No Written Description for the Breath of the Claims (“different” level of biomarker):
The claims are directed to a method of determining COVID-19 severity by assessing the levels of various biomarkers in blood. Claims 1-4 require the biomarker level to be “different” compared to a reference, whereas claim 5 requires the biomarker level specifically to be “elevated.” Claims 1-4 therefore broadly encompass methods determining COVID-19 severity by detecting any difference (i.e., an elevation or decrease) in the level of the claim-recited biomarkers in the blood, and only more narrowly specifies the level is “elevated” at claim 5. The claimed method must possess specific functions, including determining COVID-19 severity. However, the specification only sets forth “elevated” levels of the claim-recited biomarkers as potentially having the required functions; the demonstration of only “elevation” of the claim-recited biomarkers is not sufficiently representative of such a broad genus of level/amount of biomarker for determining COVID-19 disease severity (i.e., “different”) as instantly claimed.
The specification discloses that elevated levels of the claim-recited biomarkers in blood corelates with COVID-19 severity at FIGs. 2, 10-18, and 23. The only correlation that is disclosed is elevation of the claim-recited biomarkers: angiopoietin-2 (Ang-2), endothelin-1 (ET-1), soluble intercellular adhesion molecule (sICAM), soluble vascular cell adhesion molecule (sVCAM), soluble E- selectin (sE-selectin), triggering receptor expressed on myeloid cells-1 (sTREM-1), interkeulin-6 (IL-6), interleukin- 8 (IL-8), myeloperoxidase (MPO), and high-sensitivity cardiac troponin (hs-cTnl). Importantly, the specification does not disclose that a decrease (encompassed by the term “different”) in any of the claim-recited biomarkers correlates with COVID-19 severity.
The claims recite functional language of: determining COVID-19 severity by the biomarkers. However, a definition by function does not suffice to define the genus of biomarker levels because it is only an indication of what the method does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. To address this issue, a brief assessment of the state of the art of “different” biomarker levels is provided below, which shows that the genus “different biomarker level” is highly variable with respect to efficacy for determining COVID-19 severity.
Li et al. ("Interleukin-8 as a biomarker for disease prognosis of coronavirus disease-2019 patients." Frontiers in immunology 11 (2021): 602395) is directed to the identification of COVID-19 prognosis/severity biomarkers. Li et al. at abstract. Li et al. shows a panel of 40 biomarkers in patients with severe COVID-19 vs “recovered” or “normal” reference panels. Li et al. at FIG. 1. FIG. 1 shows that nearly every biomarker tested had a “different” level between the conditions. However, none of the biomarkers that showed a decreased level in the patient with severe COVID-19 (e.g., TIMP-1 in three of the four patients) was found to be predictive of COVID-19 severity; in fact, only elevated IL-8, and to a limit extent, elevated IL-6, was found to be predictive of COVID-19 severity of the 40 biomarkers tested. See e.g., Li et al. at FIG. 4 B, C. Li et al. therefore teaches it is very unpredictable which “elevated level” biomarkers may be operable to determine COVID-19 severity, let alone which “different level” biomarkers, encompassing biomarkers that decrease in level, may be operable to determine COVID-19 severity. Accordingly, significant experimentation is required to find the “different” levels of the claim-recited biomarkers that are may determine COVID-19 severity, if it is even possible.
Neither the art nor the specification provides a sufficient representative number of “different” biomarker levels to meet the written description requirement for instant claims directed to a method of determining COVID-19 severity by detecting “different” levels of the claim-recited biomarkers in general.
It is therefore unknown how the genus of “different” biomarker levels would determine COVID-19 severity. Applicant has not shown possession of a representative number of species that have the claimed function(s). The cited reference teaches that it is very unpredictable what “different” level of biomarker will determine COVID-19 disease severity. Accordingly, significant experimentation is required to find “different” biomarker levels that will work.
The specification therefore provides insufficient written description to support the genus of “different” biomarker levels encompassed by the claims.
Given all of the above, the cited reference therefore demonstrates that Applicant is not in possession of: a method of detecting COVID-19 severity by detecting a “difference” in the levels of the claim-recited biomarkers. Applicant is in possession of: a method of detecting COVID-19 severity by detecting a “elevation” in the levels of the claim-recited biomarkers.
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.
Enablement
7. Claims 1-4 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of determining COVID-19 severity by an “elevated level” of the claim-recited biomarkers, does not reasonably provide enablement for a method of determining COVID-19 severity by an “different level” of the claim-recited biomarkers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(2) The breadth of the claims:
The claims are drawn to a method of determining COVID-19 severity, “wherein a different level of at least one biomarker in the biomarker panel compared to a reference panel from a SARS-CoV-2-negative subject is indicative of COVID-19 severity.” Claim 5 further recites that the “different level” is an elevated. Claims 1-4 are therefore broad and encompass determining COVID-19 severity by “different levels” of the claim-recited biomarkers, including elevated and decreased levels of the biomarkers.
(5) The predictability or unpredictability of the art:
The state of the art indicates it is very unpredictable how well members of the genus “different level” of biomarker will determine COVID-19 severity in a subject.
Li et al. ("Interleukin-8 as a biomarker for disease prognosis of coronavirus disease-2019 patients." Frontiers in immunology 11 (2021): 602395) is directed to the identification of COVID-19 prognosis/severity biomarkers. Li et al. at abstract. Li et al. shows a panel of 40 biomarkers in patients with severe COVID-19 vs “recovered” or “normal” reference panels. Li et al. at FIG. 1. FIG. 1 shows that nearly every biomarker tested had a “different” level between the conditions. However, none of the biomarkers that showed a decreased level in the patient with severe COVID-19 (e.g., TIMP-1 in three of the four patients) was found to be predictive of COVID-19 severity; in fact, only elevated IL-8, and to a limit extent, elevated IL-6, was found to be predictive of COVID-19 severity of the 40 biomarkers tested. See e.g., Li et al. at FIG. 4 B, C. Li et al. therefore teaches it is very unpredictable which “elevated level” biomarkers may be operable to determine COVID-19 severity, let alone which “different level” biomarkers, encompassing biomarkers that decrease in level, may be operable to determine COVID-19 severity.
Therefore, without actually performing the required experiments, it is unpredictable which members of the instantly claimed genus “different level” of the claim-recited biomarkers can determine COVID-19 severity in a subject.
6) the amount of direction or guidance provided by the inventor:
The specification discloses that elevated levels of the claim-recited biomarkers in blood corelates with COVID-19 severity at FIGs. 2, 10-18, and 23. The only correlation that is disclosed is elevation of the claim-recited biomarkers: angiopoietin-2 (Ang-2), endothelin-1 (ET-1), soluble intercellular adhesion molecule (sICAM), soluble vascular cell adhesion molecule (sVCAM), soluble E- selectin (sE-selectin), triggering receptor expressed on myeloid cells-1 (sTREM-1), interkeulin-6 (IL-6), interleukin- 8 (IL-8), myeloperoxidase (MPO), and high-sensitivity cardiac troponin (hs-cTnl). Importantly, the specification does not disclose that a decrease (encompassed by the term “different”) in any of the claim-recited biomarkers correlates with COVID-19 severity.
Given the evidence above, one of skill in the art could not reasonably extrapolate the instant findings regarding determining COVID-19 severity by the “elevated levels” of the claim-recited biomarkers to determining COVID-19 severity by “different levels” of the claim-recited biomarkers, including decreased levels of the claim-recited biomarkers. It would also be undue experimentation to confirm if decreased levels of any of the biomarkers encompassed by the claims could determine the severity of COVID-19.
8) the quantity of experimentation needed to make or use the invention:
It would be undue experimentation to make or use the invention encompassed by the breadth of the claims because each of the claim-recited biomarkers would need to be re-tested to determine if in some circumstances a “decreased level” and therefore a “different level” of the biomarker was able to detect COVID-19 severity; Applicant has only shown that “elevated levels” of the claim-recited biomarkers can determine COVID-19 severity, and Li et al. shows that it is very unpredictable what biomarkers have “decreased levels” that may determine COVID-19 severity, if it is even possible.
In conclusion, the claimed invention does not provide enablement for determining COVID-19 severity with the genus “different level” of the claim-recited biomarkers. The claimed invention only provides enablement for the species “elevated level” of the claim-recited biomarkers. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claim Rejections - 35 USC § 101
8. 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.
9. Claims 1-5 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. Claims 1-5 are directed to a judicial exception. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the reasons set forth below.
The claims are drawn to a method of determining Coronavirus Disease 2019 (COVID-19) severity in a subject, the method comprising: obtaining a circulating blood sample from the subject; obtaining a biomarker panel comprising one or more of angiopoietin-2 (Ang-2), endothelin-1 (ET-1), soluble intercellular adhesion molecule (sICAM), soluble vascular cell adhesion molecule (sVCAM), soluble E- selectin (sE-selectin), triggering receptor expressed on myeloid cells-1 (sTREM-1), interkeulin-6 (IL-6), interleukin- 8 (IL-8), myeloperoxidase (MPO), and high-sensitivity cardiac troponin (hs-cTnl); wherein a different level of at least one biomarker in the biomarker panel compared to a reference panel from a SARS-CoV-2-negative subject is indicative of COVID-19 severity.
The claim recites or requires a series of steps/acts, i.e., (i) obtaining a circulating blood sample and obtaining a biomarker panel; and (ii) comparing the level of the biomarkers in the sample to a reference panel in order to; (iii) detect/indicate COVID-19 severity. Thus, the claim is directed to a process, which is one of the statutory categories of invention. The wherein clause states “wherein a different level of at least one biomarker in the biomarker panel compared to a reference panel from a SARS-CoV-2-negative subject is indicative of COVID-19 severity.” The wherein clause describes a correlation or relationship between the host immune system biomarkers in a circulating blood sample and COVID-19 severity. This limitation sets forth a judicial exception because this type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo. Additionally, the correlation/relationship between the recited biomarkers and COVID-19 is known in the art. For instance, Gustafson et al. ("Overcoming barriers: the endothelium as a linchpin of coronavirus disease 2019 pathogenesis?" Arteriosclerosis, thrombosis, and vascular biology 40.8 (August 2020): 1818-1829) at Table 3 suggests biomarkers: Ang-2 and sICAM-1are associated with COVID-19 severity. Additionally, steps of “comparing” and “detecting/indicating” are abstract ideas, and thus the claims are directed towards a judicial exception. The steps of comparing and detecting/indicating are recited at a high level of generality that imposes no limits on how the steps are accomplished. When interpreting the claim during examination, it is apparent that the steps of comparing and detecting/indicating could be performed by a human using mental steps or basic critical thinking. Similar mental processes have been held by the courts to be abstract ideas, e.g., collecting and comparing known information in Classen, or comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC. The specific information that is being compared (e.g., protein levels of biomarkers in blood) merely narrows the abstract idea, which does not make the comparison step less abstract and is not sufficient to provide eligibility on its own. Thus, the claim is directed to an abstract idea.
The claims recite elements/steps in addition to the judicial exception(s) that are recited at a high level of generality, must be used/taken by others to apply the judicial exception(s), are well-understood, purely conventional or routine, are insignificant extra-solution activity, (e.g., are merely appended to the judicial exception(s) and amount to nothing more than a mere field of use). For instance, dependent claim 5 recites “wherein an elevated level of at least one biomarker is indicative of COVID-19 severity.” However, detecting an elevated level of a biomarker is routine and conventional and impose no meaningful limit on the method.
The “detecting/indicating” and “comparing” steps simply tell the relevant audience about the relevant natural laws, at most adding a suggestion that the person determining COVID-19 severity should take those laws into account when determining the COVID-19 severity. The steps also tell the relevant audience to detect and compare the level of the biomarkers through whatever process the relevant audience wishes to use. The claims inform a relevant audience about certain laws of nature; any 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 their parts taken separately. Taken together, the claims do not amount to significantly more than the natural law itself.
Consideration of the additional elements as a combination also adds no other meaningful limitations to the exception not already present when the elements are considered separately. Unlike the eligible claim in Diehr in which the elements limiting the exception are individually conventional, but taken together act in concert to improve a technical field, the claim here does not invoke any of the considerations that courts have identified as providing significantly more than an exception. Even when viewed as a combination, the additional elements fail to transform the exception into a patent eligible application of that exception. Thus, the claim as a whole does not amount to significantly more than the exception itself.
Claim Rejections - 35 USC § 102
10. 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.
Claims 1-2 and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Smadja et al. ("Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients." Angiogenesis 23.4 (2020): 611-620.)
Claim 1 is drawn to a method of determining Coronavirus Disease 2019 (COVID-19) severity in a subject, the method comprising: obtaining a circulating blood sample from the subject; obtaining a biomarker panel comprising one or more of angiopoietin-2 (Ang-2), endothelin-1 (ET-1), soluble intercellular adhesion molecule (sICAM), soluble vascular cell adhesion molecule (sVCAM), soluble E- selectin (sE-selectin), triggering receptor expressed on myeloid cells-1 (sTREM-1), interkeulin-6 (IL-6), interleukin- 8 (IL-8), myeloperoxidase (MPO), and high-sensitivity cardiac troponin (hs-cTnl); wherein a different level of at least one biomarker in the biomarker panel compared to a reference panel from a SARS-CoV-2-negative subject is indicative of COVID-19 severity.
Claim 2 is drawn to the method of claim 1, wherein the biomarker panel comprises Ang-2.
Claim 5 is drawn to the method of claim 1, wherein an elevated level of at least one biomarker is indicative of COVID-19 severity.
Smadja et al. is directed to the analysis of endothelial and angiogenic biomarkers in the circulating blood of COVID-19 patients to determine COVID-19 severity and the need for intensive care unit (ICU) referral. Smadja et al. at abstract. Smadja et al. obtains a circulating blood sample and a biomarker panel comprising Ang-2 and sE-Selectin biomarkers. See e.g., Smadja et al at FIG. 1. Smadja et al. compares the sE-selectin biomarker level to a control (i.e., “reference panel” having a different level of sE-selectin biomarker) to determine ICU vs non-ICU severity of COVID 19 (claims 1-2), and shows that elevated sE-selectin compared to the reference indicates ICU (i.e., high severity) vs non-ICU severity of COVID-19 (claim 5). See e.g., Smadja et al. at FIG. 2.
Accordingly, Smadja et al. anticipates instant claims 1-2 and 5.
Claim Rejections - 35 USC § 103
11. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
12. 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.
13. Claims 1-3 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Smadja et al. in view of Gueant et al. ("Blood myeloperoxidase‐DNA, a biomarker of early response to SARS‐CoV‐2 infection?." Allergy 76.3 (2020): 892.).
Claim 1 is drawn to a method of determining Coronavirus Disease 2019 (COVID-19) severity in a subject, the method comprising: obtaining a circulating blood sample from the subject; obtaining a biomarker panel comprising one or more of angiopoietin-2 (Ang-2), endothelin-1 (ET-1), soluble intercellular adhesion molecule (sICAM), soluble vascular cell adhesion molecule (sVCAM), soluble E- selectin (sE-selectin), triggering receptor expressed on myeloid cells-1 (sTREM-1), interkeulin-6 (IL-6), interleukin- 8 (IL-8), myeloperoxidase (MPO), and high-sensitivity cardiac troponin (hs-cTnl); wherein a different level of at least one biomarker in the biomarker panel compared to a reference panel from a SARS-CoV-2-negative subject is indicative of COVID-19 severity.
Claim 2 is drawn to the method of claim 1, wherein the biomarker panel comprises Ang-2.
Claim 3 is drawn to the method of claim 1, wherein the biomarker panel comprises Ang-2 and MPO.
Claim 5 is drawn to the method of claim 1, wherein an elevated level of at least one biomarker is indicative of COVID-19 severity.
Smadja et al. is directed to the analysis of cardiovascular / endothelial-related biomarkers in the circulating blood of COVID-19 patients to determine COVID-19 severity and the need for intensive care unit (ICU) referral. Smadja et al. at abstract. Smadja et al. obtains a circulating blood sample and a biomarker panel comprising Ang-2 and sE-Selectin biomarkers. See e.g., Smadja et al at FIG. 1. Smadja et al. compares the sE-selectin biomarker level to a control (i.e., “reference panel” having a different level of sE-selectin biomarker) to determine ICU vs non-ICU severity of COVID 19 (claims 1-2), and shows that elevated sE-selectin compared to the reference indicates ICU (i.e., high severity) vs non-ICU severity of COVID-19 (claim 5). See e.g., Smadja et al. at FIG. 2.
Smadja et al. does not teach including MPO in the panel, i.e., claim 3.
Gueant et al. is directed to MPO as an early biomarker of COVID-19 infection. Gueant et al. at title. Gueant et al. shows that the MPO biomarker is elevated in symptomatic COVID-19 patients even before it is detectable by RT-PCR. Gueant et al. at FIG. 1.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the COVID-19 severity biomarkers as taught by Smadja et al. to include the MPO biomarker as taught by Gueant et al. because Smadja et al. teach the aim of their study “was to identify, in COVID-19 patients with criteria of hospitalization, soluble circulating endothelial and/or angiogenic markers at admission that could predict the need for hospitalization in intensive care unit (ICU) – i.e., respiratory failure and requiring mechanical ventilation – and anticipate subsequent disease worsening.” Smadja et al. at introduction and Gueant et al. suggests that blood level of MPO-DNA complexes could be a useful biomarker for early phase of SARS-CoV-2 infection (page 895). The person of ordinary skill in the art would be motivated to include MPO as a biomarker for determining COVID-19 severity because including MPO would increase the power of the panel by helping to confirm the patient even has COVID-19, and therefore may be at risk of having worsening COVID-19 requiring ICU admission. There would be a reasonable expectation of success that including MPO in the panel would improve the panel because Guent et al. further shows that some symptomatic COVID-19 infected patients do not test positive by RT-PCR, but do show elevated MPO biomarker, and so including MPO will improve the ability to diagnose COVID-19 severity.
Furthermore, it is obvious to combine prior art elements according to known methods to yield predictable results. In this case, each element (e.g., the COVID-19 severity biomarkers of Smadja et al. and MPO biomarker of Gueant et al.) merely performs the same function as it does separately. As discussed above, the expectation of success with the combination is reasonable. Accordingly, Smadja et al. in view of Gueant et al. renders instant claims 1-3 and 5 obvious.
14. Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Smadja et al. in view of Gueant et al. as applied to claims 1-3 and 5 above, and further in view of Van Singer et al. ("COVID-19 risk stratification algorithms based on sTREM-1 and IL-6 in emergency department." Journal of Allergy and Clinical Immunology 147.1 (2021): 99-106); disclose Ang-2, sTREM-1, IL-6, and IL-8 as having increased plasma concentration with increased COVID-19 severity; Farhangrazi et al. ("Elevated circulating endothelin-1 as a potential biomarker for high-risk COVID-19 severity." Precis Nanomed 3 (2020): 622-8); discloses ET-1 as having increased plasma concentration with increased COVID-19 severity; Gustafson et al. ("Overcoming barriers: the endothelium as a linchpin of coronavirus disease 2019 pathogenesis?" Arteriosclerosis, thrombosis, and vascular biology 40.8 (August 2020): 1818-1829); discloses sICAM-1, VCAM-1, and troponin as potentially having increased plasma concentration with increased COVID-19 severity; and Atallah et al. ("A marker of systemic inflammation or direct cardiac injury: should cardiac troponin levels be monitored in COVID-19 patients?." European Heart Journal-Quality of Care and Clinical Outcomes 6.3 (2020): 204-207); specifically discloses hs-cTnI (high sensitivity cardiac troponin) as having increased plasma concentration with increased COVID-19 severity.
Claim 4 is drawn to method of claim 1, wherein the biomarker panel comprises Ang-2, ET-1, sICAM-1, sVCAM- 1, sE-Selectin, sTREM-1, IL-6, IL-8, MPO and hs-cTnl.
The teachings of Smadja et al. in view of Gueant et al. have been disclosed above.
Smadja et al. in view of Gueant et al. does not explicitly disclose including the ET-1, sICAM-1, sVCAM-1, sTREM-1, IL-6, IL-8, and hs-cTnl biomarkers.
Van Singer et al. is directed to cardiovascular / endothelial-related biomarkers and how they may be useful for determining to COVID-19 adverse outcomes / severity. Van Singer et al. at abstract. Van Singer et al. discloses that the plasma level of each of Ang-2, IL-6, IL-8, and sTREM-1 is elevated proportionally to the severity of COVID-19; e.g., FIG. 1 shows that mild, medium, and high severity COVID-19 results in a proportional increase in the plasma levels of each of Ang-2, IL-6, IL-8, and sTREM-1.
Farhangrazi et al. ("Elevated circulating endothelin-1 as a potential biomarker for high-risk COVID-19 severity”) is directed to the cardiovascular / endothelial-related biomarker ET-1 as a potential biomarker for COVID-19 severity. Farhangrazi et al. at title. Farhangrazi et al. teaches that: “Endothelin-1 (ET-1) is the most potent vasoconstrictor of the human cardiovascular system and a culprit of endothelial dysfunction. Elevated circulating ET-1 levels are a predictor of cardiovascular disease status […] Here, we propose elevated circulating ET-1 levels as a plausible biomarker and prognostic tool in predicting individuals at high risk of developing severe COVID-19.” Farhangrazi et al. abstract.
Gustafson et al. is directed to cardiovascular / endothelial-related biomarkers and how they may be useful for determining to COVID-19 course / severity. Gustafson et al. at title, abstract. Gustafson et al. teaches that the endothelium has a “potentially critical role as a mediator of [COVID-19] disease severity,” and suggests that circulating endothelial-derived biomarkers that predict the development and/or outcome of ARDS (i.e., Table 3) provides a starting point for COVID-19 biomarker development. Gustafson et al. at “conclusions and perspectives for future research” and pg. 1823, right col. Table 3 discloses biomarkers: Ang-2, sICAM-1; and the text further discloses biomarkers: sE-Selectin and VCAM-1. Table 1 further discloses IL-6 and troponin as “emerging biomarkers of poor cardiovascular outcomes in COVID-19.”
Gustafson et al. does not explicitly disclose that the troponin may be hs-cTnI (high-sensitivity cardiac troponin).
Atallah et al. is an opinion piece on whether cardiac troponin levels should be monitored in COVID-19 patients. Atallah et al. at title. Atallah et al. summarizes the results of COVID-19 cardiac-implicated cases at Table 1, showing that hs-cTnl levels are elevated in the blood of patients with severe COVID-19. Atallah et al. concludes with recommendation 4: “Since the studies referenced above reported minimal elevation of troponin levels in surviving patients, use of hs-cTnI assays can provide a highly sensitive test to potentially rule out sever complications and a poor prognosis early on, and may prove useful in last-resort and limited-resources situations that demand triaging of COVID-19 patients.” Therefore, Atallah et al. teaches that the hs-cTnI biomarker is better than the general troponin biomarker taught by Gustafson because it is more sensitive and can therefore provide an earlier diagnosis of COVID-19 severity.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the COVID-19 severity biomarkers as taught by Smadja et al. and Gueant et al. (i.e., Ang-2, sE-Selectin, and MPO) to further include the IL-6, IL-8, and sTREM-1 biomarkers as taught by Van Singer et al.; the ET-1 biomarker as taught by Farhangrazi et al.; the sICAM-1, VCAM-1, and troponin biomarker as taught by Gustafson et al.; and specifically the better hs-cTnl biomarker as taught by Atallah et al. because each of Smadja et al., Van Singer et al., Farhangrazi et al., Gustafson et al., and Atallah et al. teach the association between cardiovascular / endothelial-related biomarkers and COVID-19 severity. Having the original inspiration from Smadja et al., teaching the link between cardiovascular / endothelial-related biomarkers and COVID-19 severity (e.g., “In conclusion, our data strongly support the relevance of levels of biomarker of endothelial dysfunction in COVID-19 patients at hospital admission, since vascular disorders and thrombosis seem to be a crucial point”), the person of ordinary skill in the art would be motivated to try including the additional cardiovascular / endothelial-related biomarkers taught by Van Singer et al., Farhangrazi et al., Gustafson et al., and Atallah et al. to further improve the sensitivity of the panel, especially since each of these references also suggest the specific cardiovascular / endothelial biomarkers may have COVID-19 severity diagnostic value. Smadja et al. taught that “Angiopoietin-2 was the best biomarker to predict transfer to the ICU,” i.e., better than sE-Selectin, and so there is a reasonable expectation of success that including the additional cardiovascular / endothelial-related biomarkers may improve on the sensitivity of Ang-2 / sE-Selectin to determine COVID-19 severity.
Furthermore, it is obvious to combine prior art elements according to known methods to yield predictable results. In this case, each element (e.g., the COVID-19 severity biomarkers) merely performs the same function as it does separately. As discussed above, the expectation of success with the combination is reasonable.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the method of Smadja et al in view of Gueant et al to additionally add other biomarkers to the panel used in the claim method because the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art.
Therefore, claims 1-5 are rendered obvious by Smadja et al. in view of Gueant et al., in view of Van Singer et al., in view of Farhangrazi et al., in view of Gustafson et al., and in view of Atallah et al.
Pertinent Art
15. The prior art made of record and not relied upon is considered pertinent to Applicant’s disclosure:
Xiong, Shiqin, et al. ("Interleukin-1RA mitigates SARS-CoV-2–induced inflammatory lung vascular leakage and mortality in humanized K18-hACE-2 mice." Arteriosclerosis, thrombosis, and vascular biology 41.11 (2021): 2773-2785; cited in IDS of March 16, 2023); further discloses MPO’s association with COVID-19 infection.
Conclusion
16. No claim is allowed.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
