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 correspondence filed August 17, 2026, is acknowledged. In response to the Restriction Requirement of June 17, 2026, Applicant has elected the invention of Group I, claims 1, 3-4, 6-7, 21-28, and 30 without traverse. Therefore, claims 1, 3-4, 6-7, and 21-30 are pending; claim 29 is presently withdrawn as being drawn to the non-elected invention; and claims 1, 3-4, 6-7, 21-28, and 30 are presently subject to examination.
Information Disclosure Statement
3. The listing of references in the specification (e.g., pg. 27-31) 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.
The references should be placed on an information disclosure statement if Applicant would like them 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., “APACHE” at page 2, ln. 20), which is a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology whenever possible; furthermore the terms 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 title is objected to referring in the alternative to compositions (for treating sepsis). The instant claims are all directed to methods for treating sepsis, and there are no claims directed to compositions for treating sepsis. Appropriate correction is required.
Claim Objections
5. Claim 30 is objected to because of the following informalities: Claim 30 recites “at least two sepsis biomarker,” with the term biomarker being in singular form. The term biomarker[s] should be in plural form to be grammatically correct. Appropriate correction is required.
Claim Rejections - 35 USC § 112
6. 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
7. Claims 1, 3-4, 6-7, 21-28, and 30 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 Breadth of the Claims: methods for treating sepsis with sepsis biomarker inhibitors based on APACHE III score or correlations of biomarker levels to sepsis. Applicant is not in possession of any methods of treating sepsis.
Claim 1 recites a method of treating sepsis in patients having elevated APACHE III score by administering at least one biomarker inhibitor. Claim 3 recites a method of treating sepsis by determining an elevated level of at least one sepsis biomarker; and administering at least one biomarker inhibitor. The dependent claims further recite elevated or lower levels of various biomarkers (at least 27 distinct biomarkers); and administering corresponding biomarker inhibitors.
The claims therefore broadly encompass identifying various biomarkers associated with or correlating to sepsis; and then treating the sepsis by administering an inhibitor of the biomarker.
The specification discloses a study of 280 sepsis patients, with APACHE III scores and the levels of 61 biomarkers ascertained and compared to control subjects (see Example—Subjects). The tables and figures show various correlations and statistical significance of the biomarker levels to bacterial sepsis, viral sepsis, and between the various biomarkers. The specification concludes: “Our study highlights two potential therapeutic targets in sepsis, i.e. the significantly increased LIGHT levels and the highly variable IL-18 levels across a subset of patients with septicemia” at pg. 27, ln. 13-15; and “The lack of correlation between LIGHT and IL-18 levels, as well as different correlations with other biomarkers, suggests independent and distinct roles of LIGHT and IL-18 in sepsis and that therapy directed against both of these cytokines could provide a therapeutic effect” at pg. 27, ln. 27-30 (emphasis added). The specification does not disclose any treatment of sepsis, only correlations of the various biomarkers to sepsis.
The claims require that sepsis be treated with sepsis biomarker inhibitors. The specification defines the term “treatment” to include e.g., inhibiting the disease at pg. 14, ln. 33. However, the specification does not disclose any treatment of sepsis, let alone with the biomarker inhibitors encompassed by the claims. The specification only presents biomarkers that, in Applicant’s own words, have “potential” and “could [i.e., maybe] provide therapeutic effect” based on the ascertained correlations with sepsis. Therefore, the breadth of the claims—requiring treatment, and specifically with inhibitors of the biomarkers—is not commensurate with the specification’s disclosure. To address this issue, a brief assessment of the state of the art of sepsis biomarker inhibitors and effective treatment of sepsis based on the biomarkers is made herein, which shows that it is very unpredictable that inhibiting any of the instantly claimed sepsis biomarkers may result in treatment of sepsis because: the correlation of a biomarker to a disease is not at all the same as the biomarker causing the disease (i.e., suggesting inhibiting the biomarker may treat the disease).
Marshall ("Why have clinical trials in sepsis failed?." Trends in molecular medicine 20.4 (2014): 195-203) is an opinion piece on sepsis clinical trial failures (see the title). Marshall summarizes at the introduction: “More than 100 randomized clinical trials have tested the hypothesis that modulating the septic response to infection can improve survival. With one short-lived exception, none of these has resulted in new treatments.” Marshall further discusses at pg. 195, right col., first para. that these failures include attempts to neutralize inflammatory mediators, e.g., IL-1 (a biomarker). Marshall explains that: “There is not a single simple explanation for the disconnect between promise and reality in sepsis research” at pg. 195, right col., third para. Marshall further explains that: “These processes [sepsis] are enormously complex. Using a reductionist animal model of acute inflammation, the administration of a bolus infusion of endotoxin to a mouse, it has been shown that more than 100 discrete biochemical species are necessary for disease evolution because their ablation or administration alters mortality risk (Table 2). In a corresponding human model, low dose endotoxin challenge alters the expression of 3714 genes in circulating leukocytes. A conclusion from this body of work is that inflammation is a complex interdependent process whose deleterious effects can be ascribed to multiple host-derived biochemical mediators. A corollary to this conclusion is that it is improbable that modulating the activity of any one of these will have more than a modest effect on the clinical course of illness.” Marshall at pg. 196, last paragraph. Therefore, Marshall demonstrates that the etiology of sepsis is complex, and therefore to treat sepsis, e.g., by inhibiting biomarkers associated with the sepsis, will require experimentation to identify a combination of specific inhibitors that may or may not work. Applicant has not performed any of the required experiments to determine which may work, but rather only has identified biomarkers that have, in Applicant’s own words, “promise.”
This is further corroborated by Cho et al. ("Biomarkers of sepsis." Infection & chemotherapy 46.1 (2014): 1-12), a review of the use of sepsis biomarkers (see the title). Cho et al. explain at the abstract: “More than 170 biomarkers have been identified as useful for evaluating sepsis, including C-reactive protein, procalcitonin, various cytokines, and cell surface markers. Recently, studies have reported on the usefulness of biomarker-guided antibiotic stewardships. However, the other side of these numerous biomarkers is that no novel single laboratory marker can diagnose, predict, and track the treatment of sepsis.” Cho et al. further explain at pg. 3, left col., first para. regarding cytokine sepsis biomarkers that: “TNF-α, IL-1β, and IL-6 are cytokines responsible for mediation of the initial innate immune system response to injury or infection. These proinflammatory cytokines contribute to fever, activate endothelial cells, attract circulating polymorphonuclear cells (PMNs), and enter the circulatory system. Studies have demonstrated increased blood cytokine levels in patients with sepsis. However, levels of these cytokines also increase after trauma, surgery, stroke, or with autoimmune diseases. Use of these inflammatory cytokines to diagnosis sepsis is difficult because they are nonspecific and unable to differentiate infection from inflammation. TNF-α and IL-6 levels have been reported to be related to organ damage and mortality, making them potentially useful prognosis predictors. However, a clinical trial of pretreatment with polyclonal ovine anti-TNF fragment antigen binding fragments (CytoFab) showed no difference in 28-day mortality.” Cho et al. therefore show that although a biomarker associated with sepsis (e.g., TNF-α) was known to be elevated, inhibiting the biomarker (e.g., with CytoFab) did not result in “treatment.” For example, if TNF-α—although correlated with sepsis—is not solely responsible for sepsis etiology, inhibiting the TNF-α by itself will be insufficient to treat the disease, if it is even causal to the disease rather than a byproduct of the disease.
Therefore, without performing any of the required experiments, it is unpredictable how inhibition of the various claim-recited biomarkers may effectuate a treatment for sepsis. Neither the art nor the specification provides a sufficient representative number of examples where inhibiting a biomarker associated with sepsis effectuates sepsis treatment to meet the written description of instant claims directed to the treatment of sepsis. This is at least because: correlation of a biomarker to a disease does not indicate that the biomarker has a causal relationship to the disease; and furthermore, the art indicates that treatment, if it is even possible, will require administering very specific combination of sepsis biomarker inhibitors. Applicant has not demonstrated treatment of sepsis with a single biomarker inhibitor—let alone with the combination of biomarker inhibitors that would be required to treat sepsis, if it is even possible. It is therefore wholly unknown how inhibition of the various biomarkers will treat sepsis. Applicant has not demonstrated possession of any of the instantly claimed subject matter.
Given all of the above, Applicant does not have possession for methods of treating sepsis by inhibiting the instantly claimed biomarkers. Applicant is not in possession of any of the instantly claimed subject matter.
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
8. Claims 1, 3-4, 6-7, 21-28, and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The specification does not reasonably provide enablement for methods of treating sepsis by administering inhibitors of the biomarkers.
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 methods of treating sepsis in patients having elevated APACHE III score by administering at least one biomarker inhibitor (i.e., claim 1); and methods of treating sepsis by determining an elevated level of at least one sepsis biomarker; and administering at least one biomarker inhibitor (i.e., claim 3). The dependent claims further recite elevated or lower levels of various biomarkers (at least 27 distinct biomarkers); and administering corresponding biomarker inhibitors.
The claims are therefore broad and encompass that any combination of detected biomarkers will indicate a sepsis patient is treatable by administering an effective amount of an inhibitor of the corresponding sepsis biomarker(s).
(5) The predictability or unpredictability of the art:
The state of the art indicates that it is very unpredictable how well the various biomarkers correlating to sepsis may translate into sepsis therapeutics.
It is unpredictable which biomarkers are causally related to sepsis, let alone which biomarkers indicate sepsis is treatable by furthermore inhibiting the sepsis biomarker; Applicant has not shown how to make and use any sepsis biomarker inhibitor that treats sepsis.
The claims require that sepsis be treated with sepsis biomarker inhibitors. The specification defines the term “treatment” to include e.g., inhibiting the disease at pg. 14, ln. 33. However, the specification does not disclose any treatment of sepsis, let alone with the biomarker inhibitors encompassed by the claims. The specification only presents biomarkers that, in Applicant’s own words, have “potential” and “could [i.e., maybe] provide therapeutic effect” based on the ascertained correlations with sepsis. In view of this uncertainty, a brief assessment of the state of the art of sepsis biomarker inhibitors and effective treatment of sepsis based on the biomarkers is made herein, which shows that it is very unpredictable that inhibiting any of the instantly claimed sepsis biomarkers may result in treatment of sepsis because: the correlation of a biomarker to a disease is not at all the same as the biomarker causing the disease (i.e., suggesting inhibiting the biomarker may treat the disease).
Marshall ("Why have clinical trials in sepsis failed?." Trends in molecular medicine 20.4 (2014): 195-203) is an opinion piece on sepsis clinical trial failures (see the title). Marshall summarizes at the introduction: “More than 100 randomized clinical trials have tested the hypothesis that modulating the septic response to infection can improve survival. With one short-lived exception, none of these has resulted in new treatments.” Marshall further discusses at pg. 195, right col., first para. that these failures include attempts to neutralize inflammatory mediators, e.g., IL-1 (a biomarker). Marshall explains that: “There is not a single simple explanation for the disconnect between promise and reality in sepsis research” at pg. 195, right col., third para. Marshall further explains that: “These processes [sepsis] are enormously complex. Using a reductionist animal model of acute inflammation, the administration of a bolus infusion of endotoxin to a mouse, it has been shown that more than 100 discrete biochemical species are necessary for disease evolution because their ablation or administration alters mortality risk (Table 2). In a corresponding human model, low dose endotoxin challenge alters the expression of 3714 genes in circulating leukocytes. A conclusion from this body of work is that inflammation is a complex interdependent process whose deleterious effects can be ascribed to multiple host-derived biochemical mediators. A corollary to this conclusion is that it is improbable that modulating the activity of any one of these will have more than a modest effect on the clinical course of illness.” Marshall at pg. 196, last paragraph. Therefore, Marshall demonstrates that the etiology of sepsis is complex, and therefore to treat sepsis, e.g., by inhibiting biomarkers associated with the sepsis, will require experimentation to identify a combination of specific inhibitors that may or may not work. Applicant has not performed any of the required experiments to determine which may work, but rather only has identified biomarkers that have, in Applicant’s own words, “promise.”
This is further corroborated by Cho et al. ("Biomarkers of sepsis." Infection & chemotherapy 46.1 (2014): 1-12), a review of the use of sepsis biomarkers (see the title). Cho et al. explain at the abstract: “More than 170 biomarkers have been identified as useful for evaluating sepsis, including C-reactive protein, procalcitonin, various cytokines, and cell surface markers. Recently, studies have reported on the usefulness of biomarker-guided antibiotic stewardships. However, the other side of these numerous biomarkers is that no novel single laboratory marker can diagnose, predict, and track the treatment of sepsis.” Cho et al. further explain at pg. 3, left col., first para. regarding cytokine sepsis biomarkers that: “TNF-α, IL-1β, and IL-6 are cytokines responsible for mediation of the initial innate immune system response to injury or infection. These proinflammatory cytokines contribute to fever, activate endothelial cells, attract circulating polymorphonuclear cells (PMNs), and enter the circulatory system. Studies have demonstrated increased blood cytokine levels in patients with sepsis. However, levels of these cytokines also increase after trauma, surgery, stroke, or with autoimmune diseases. Use of these inflammatory cytokines to diagnosis sepsis is difficult because they are nonspecific and unable to differentiate infection from inflammation. TNF-α and IL-6 levels have been reported to be related to organ damage and mortality, making them potentially useful prognosis predictors. However, a clinical trial of pretreatment with polyclonal ovine anti-TNF fragment antigen binding fragments (CytoFab) showed no difference in 28-day mortality.” Cho et al. therefore show that although a biomarker associated with sepsis (e.g., TNF-α) was known to be elevated, inhibiting the biomarker (e.g., with CytoFab) did not result in “treatment.” For example, if TNF-α—although correlated with sepsis—is not solely responsible for sepsis etiology, inhibiting the TNF-α by itself will be insufficient to treat the disease, if it is even causal to the disease rather than a byproduct of the disease.
Given all the above, the cited references demonstrate that it is very unpredictable which of the claim-recited sepsis biomarkers have any causal relationship to sepsis; or furthermore indicate that the sepsis is treatable with an inhibitor of the biomarker(s). Applicant has not performed the required experiments to teach one of ordinary skill in the art how to make and use a single species of the biomarker inhibitors—that treats sepsis—encompassed by the claims.
(6) the amount of direction or guidance provided by the inventor:
The specification only discloses correlations of the various biomarkers with sepsis status. The specification fails to disclose any attempts to treat sepsis, let alone with an inhibitor of any of the biomarkers. Given all of the above, one of skill in the art could not reasonably extrapolate the instant findings regarding correlations of biomarker levels to sepsis to the breadth of the claim-recited sepsis treatments. It would be undue experimentation to determine which biomarker inhibitors, and in what combination, may effectuate the treatment of sepsis.
(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 at least 27 biomarker inhibitors encompassed by the claims would need to be tested alone and in combination to determine which may effectuate a treatment for sepsis. This would require thousands of experiments, including experiments to determine what the effective amount of the sepsis biomarker inhibitors may be. In contrast, Applicant has not demonstrated how to make and use even a single embodiment of the claimed invention. As the above-cited references demonstrate, it is therefore highly unpredictable which of the encompassed sepsis biomarker inhibitors may treat sepsis.
In conclusion, the claimed invention does not provide enablement for methods of treating sepsis by administering biomarker inhibitors. 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 § 112(b)
9. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-4, 6-7, 21-28, and 30 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A. Claim 1 contains the trademark/trade name “APACHE.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a subject population and, accordingly, the identification/description is indefinite. Appropriate clarification and/or correction is required.
B. Claim 1 recites the limitation “to the patient” in singular form at line 4. There is insufficient antecedent basis for this limitation in the claim because line 1 of the claim refers to “in patients” in plural form. The claim could be rendered definite if, for example, “in patients” in line 1 of claim 1 was changed to “in a patient”. See e.g., claim 3. Appropriate clarification and/or correction is required.
C. Claims 21-27 recite the limitation "the at least one sepsis marker.” There is insufficient antecedent basis for this limitation in the claim. Specifically, parent claim 3 refers to a “at least one sepsis biomarker” but it is unclear whether the scope of “marker” and “biomarker” is the same, and therefore the term in the dependent claims lacks support in the parent claim. Appropriate clarification and/or correction is required.
D. The term “effective amount” in claims 1 and 3 is a relative term which renders the claim indefinite. The term “effective amount” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the amount of the sepsis biomarker inhibitor that is administered is indefinite. Appropriate clarification and/or correction is required.
The remaining claim(s) are rejected for depending from an indefinite claim.
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.
11. Claims 1 and 3 are rejected under 35 U.S.C 102 (a)(2) as anticipated by Derive et al. (WO2020065044A1; published April 2, 2020; cited in the ISR) as evidenced by Aldemir et al. ("Early phase (day 1–day 3) profile and clinical significance of circulating miR-101 and miR-146a in adult sepsis." Revista da Associação Médica Brasileira 72.6 (2026): e20252209). The earliest date to which the instant application claims priority is April 30, 2021.
Claim 1 is directed to a method of treating sepsis in patients having an elevated APACHE III score 2 standard deviations above the mean observed in control subjects or an elevated APACHE III score in the range of 200-299 indicating a need for treatment, the method comprising administering to the patient an effective amount of at least one sepsis biomarker inhibitor.
Claim 3 is directed to a method of treating sepsis in a patient in need thereof, comprising: a. determining whether the patient harbors an elevated level of at least one sepsis biomarker, and b. administering an effective amount of at least one sepsis biomarker inhibitor.
Derive et al. discloses a method for treating sepsis in patients having elevated APACHE III score or elevated level or elevated sepsis biomarker by administering at least one sepsis biomarker; and as evidenced by Aldemir et al., Derive et al. also discloses administering to patients having APACHE score 2 standard deviations above the mean observed in control subjects (e.g., claim 1).
Derive et al. is directed to the use of TREM-1 biomarker inhibitor for treating sepsis (see the abstract). Derive et al. discloses determining the level of TREM-1 biomarker for patient selection at e.g., pg. 4, ln. 6-15. Derive et al. discloses administering therapeutically effective amounts of TREM-1 inhibitor at e.g., pg. 14, ln. 10-24. Derive et al. also teaches patient selection by APACHE II or III score at e.g., pg. 9, ln. 21-26. Derive et al. describes an APACHE II score of 25 representing a 50% chance of mortality at pg. 77, ln. 17; and that APACHE III is similar to but a refinement of APACHE II at pg. 77, ln.24-26. Derive et al. selects patients having APACHE II scores of 22.3-25.1 to receive biomarker inhibitor at Table 3. Derive et al. does not explicitly disclose how many standard deviations above the mean APACHE score observed in control subjects these APACHE scores are, however Aldemir et al. is cited for its teaching that healthy controls have an APACHE II score of about 6.4 +/- 2.1 (2.1 is the standard deviation; see Aldemir et al. at Table 1). Accordingly, Derive et al. administered the biomarker inhibitor to patients having elevated APACHE score at least 2 standard deviations above the mean observed in control subjects, and Derive et al. indicates APACHE III is interchangeable with APACHE II.
Accordingly, Derive et al. as evidenced by Aldemir et al. anticipates claims 1 and 3.
Pertinent Art
12. The prior art made of record and not relied upon is considered pertinent to Applicant’s disclosure:
Holmes et al. (US20110093249A1; published April 21, 2011) discloses sepsis and inflammation biomarkers at para. [0166]: “Markers of inflammation that can be used with the systems and methods of the invention include ICAM-1, RANTES, MIP-2, MIP-1-beta, MIP-1-alpha, and MMP-3. Further markers of inflammation include adhesion molecules such as the integrins α1β1, α2β1, α3β1, α4β1, α5β1, α6β1, α7β1, α8β1, α9β1, αVβ7, α4β7, α6β4, αDβ2, αLβ2, αMβ2, αVβ3, αVβ5, αVβ6, αVβ8, αXβ2,αIIβ3, αIELbβ7, beta-2 integrin, beta-3 integrin, beta-2 integrin, beta-4 integrin, beta-5 integrin, beta-6 integrin, beta-7 integrin, beta-8 integrin, alpha-1 integrin, alpha-2 integrin, alpha-3 integrin, alpha-4 integrin, alpha-5 integrin, alpha-6 integrin, alpha-7 integrin, alpha-8 integrin, alpha-9 integrin, alpha-D integrin, alpha-L integrin, alpha-M integrin, alpha-V integrin, alpha-X integrin, alpha-IIb integrin, alphaIELb integrin; Integrin-associated Molecules such as Beta IG-H3, Melusin, CD47, MEPE, CD151, Osteopontin, IBSP/Sialoprotein II, RAGE, IGSF8; Selectins such as E-Selectin, P-Selectin, L-Selectin; and Ligands such as CD34, GlyCAM-1, MadCAM-1, PSGL-1, vitronectic, vitronectin receptor, fibronectin, vitronectin, collagen, laminin, ICAM-1, ICAM-3, BL-CAM, LFA-2, VCAM-1, NCAM, and PECAM. Further markers of inflammation include cytokines such as IFN-α, IFN-β, IFN-ε, -κ, and -τ, and -ξ IFN-ω, IFN-γ, IL29, IL28A and IL28B, IL-1, IL-1α and β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, and TCCR/WSX-1. Further markers of inflammation include cytokine receptors such as Common beta chain, IL-3 R alpha, IL-3 R beta, GM-CSF R, IL-5 R alpha, Common gamma Chain/IL-2 R gamma, IL-2 R alpha, IL-9 R, IL-2 R beta, IL-4 R, IL-21 R, IL-15 R alpha, IL-7 R alpha/CD127, IL-1ra/IL-1F3, IL-1 R8, IL-1 R1, IL-1 R9, IL-1 R11, IL-18 R alpha/IL-1 R5, IL-1 R3/IL-1 R AcP, IL-18 R beta/IL-1 R7, IL-1 R4/ST2 SIGIRR, IL-1 R6/IL-1 R rp2, IL-11 R alpha, IL-31 RA, CNTF R alpha, Leptin R, G-CSF R, LIF R alpha, IL-6 R, OSM R beta, IFN-alpha/beta R1, IFN-alpha/beta R2, IFN-gamma R1, IFN-gamma R2, IL-10 R alpha, IL-10 R beta, IL-20 R alpha, IL-20 R beta, IL-22 R, IL-17 R, IL-17 RD, IL-17 RC, IL-17B R, IL-13 R alpha 2, IL-23 R, IL-12 R beta 1, IL-12 R beta 2, TCCR/WSX-1, and IL-13 R alpha 1. Further markers of inflammation include chemokines such as CCL-1, CCL-2, CCL-3, CCL-4, CCL-5, CCL-6, CCL-7, CCL-8, CCL-9, CCL-10, CCL-11, CCL-12, CCL-13, CCL-14, CCL-15, CCL-16, CCL-17, CCL-18, CCL-19, CCL-20, CCL-21, CCL-22, CCL-23, CCL-24, CCL-25, CCL-26, CCL-27, CCL-28, MCK-2, MIP-2, CINC-1, CINC-2, KC, CINC-3, LIX, GRO, Thymus Chemokine-1, CXCL-1, CXCL-2, CXCL-3, CXCL-4, CXCL-5, CXCL-6, CXCL-7, CXCL-8, CXCL-9, CXCL-10, CXCL-11, CXCL-12, CXCL-13, CXCL-14, CXCL-15, CXCL-16, CXCL-17, XCL1, XCL2, and Chemerin. Further markers of inflammation include chemokine receptors such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9, CCR-10, CXCR3, CXCR6, CXCR4, CXCR1, CXCR5, CXCR2, Chem R23. Further markers of inflammation include Tumor necrosis factors (TNFs), such as TNFα, 4-1BB Ligand/TNFSF9, LIGHT/TNFSF14, APRIL/TNFSF13, Lymphotoxin, BAFF/TNFSF13B, Lymphotoxin beta/TNFSF3, CD27 Ligand/TNFSF7, OX40 Ligand/TNFSF4, CD30 Ligand/TNFSF8, TL1A/TNFSF15, CD40 Ligand/TNFSF5, TNF-alpha/TNFSF1A, EDA, TNF-beta/TNFSF1B, EDA-A2, TRAIL/TNFSF10, Fas Ligand/TNFSF6, TRANCE/TNFSF11, GITR Ligand/TNFSF18, and TWEAK/TNFSF12. Further markers of inflammation include TNF Superfamily Receptors such as 4-1BB/TNFRSF9, NGF R/TNFRSF16, BAFF R/TNFRSF13C, Osteoprotegerin/TNFRSF11B, BCMA/TNFRSF17, OX40/TNFRSF4, CD27/TNFRSF7, RANK/TNFRSF11A, CD30/TNFRSF8, RELT/TNFRSF19L, CD40/TNFRSF5, TACI/TNFRSF13B, DcR3/TNFRSF6B, TNF R1/TNFRSF1A, DcTRAIL R1/TNFRSF23, TNF R11/TNFRSF1B, DcTRAIL R2/TNFRSF22, TRAIL R1/TNFRSF10A, DR3/TNFRSF25, TRAIL R2/TNFRSF10B, DR6/TNFRSF21, TRAIL R3/TNFRSF10C, EDAR, TRAIL R4/TNFRSF10D, Fas/TNFRSF6, TROY/TNFRSF19, GITR/TNFRSF 18, TWEAK R/TNFRSF 12, HVEM/TNFRSF 14, and XEDAR. Further markers of inflammation include TNF Superfamily Regulators such as FADD, TRAF-2, RIP1, TRAF-3, TRADD, TRAF-4, TRAF-1, and TRAF-6. Further markers of inflammation include acute-phase reactants and acute phase proteins. Further markers of inflammation include TGF-beta superfamily ligands such as Activins, Activin A, Activin B, Activin AB, Activin C, BMPs (Bone Morphogenetic Proteins), BMP-2, BMP-7, BMP-3, BMP-8, BMP-3b/GDF-10, BMP-9, BMP-4, BMP-10, BMP-5, BMP-15/GDF-9B, BMP-6, Decapentaplegic, Growth/Differentiation Factors (GDFs), GDF-1, GDF-8, GDF-3, GDF-9 GDF-5, GDF-11, GDF-6, GDF-15, GDF-7, GDNF Family Ligands, Artemin, Neurturin, GDNF, Persephin, TGF-beta, TGF-beta, TGF-beta 3, TGF-beta 1, TGF-beta 5, LAP (TGF-beta 1), Latent TGF-beta bp1, Latent TGF-beta 1, Latent TGF-beta bp2, TGF-beta 1.2, Latent TGF-beta bp4, TGF-beta 2, Lefty, MIS/AMH, Lefty-1, Nodal, Lefty-A, Activin RIA/ALK-2, GFR alpha-1/GDNF R alpha-1, Activin RIB/ALK-4, GFR alpha-2/GDNF R alpha-2, Activin RIIA, GFR alpha-3/GDNF R alpha-3, Activin RIIB, GFR alpha-4/GDNF R alpha-4, ALK-1, MIS R11, ALK-7, Ret, BMPR-IA/ALK-3, TGF-beta R1/ALK-5, BMPR-IB/ALK-6, TGF-beta R11, BMPR-II, TGF-beta RIIb, Endoglin/CD105, and TGF-beta RIII. Further markers of inflammation include TGF-beta superfamily Modulators such as Amnionless, NCAM-1/CD56, BAMBI/NMA, Noggin, BMP-1/PCP, NOMO, Caronte, PRDC, Cerberus 1, SKI, Chordin, Smad1, Chordin-Like 1, Smad2, Chordin-Like 2, Smad3, COCO, Smad4, CRIM1, Smad5, Cripto, Smad7, Crossveinless-2, Smad8, Cryptic, SOST, DAN, Latent TGF-beta bp1, Decorin, Latent TGF-beta bp2, FLRG, Latent TGF-beta bp4, Follistatin, TMEFF1/Tomoregulin-1, Follistatin-like 1, TMEFF2, GASP-1/WFIKKNRP, TSG, GASP-2/WFIKKN, TSK, Gremlin, and Vasorin. Further markers of inflammation include EGF Ligands such as Amphiregulin, LRIG3, Betacellulin, Neuregulin-1/NRG1, EGF, Neuregulin-3/NRG3, Epigen, TGF-alpha, Epiregulin, TMEFF1/Tomoregulin-1, HB-EGF, TMEFF2, and LRIG1. Further markers of inflammation include EGF R/ErbB Receptor Family, such as EGF R, ErbB3, ErbB2, and ErbB4. Further markers of inflammation include Fibrinogen. Further markers of inflammation include SAA. Further markers of inflammation include glial markers, such as alpha.1-antitrypsin, C-reactive protein (CRP), α2-macroglobulin, glial fibrillary acidic protein (GFAP), Mac-1, and F4/80. Further markers of inflammation include myeloperoxidase. Further markers of inflammation include Complement markers such as C3d, C1q, C5, C4d, C4 bp, and C5a-C9. Further markers of inflammation include Major histocompatibility complex (MHC) glycoproteins, such as HLA-DR and HLA-A,D,C. Further markers of inflammation include Microglial markers, such as CR3 receptor, MHC I, MHC II, CD 31, CD11a, CD11b, CD11c, CD68, CD45RO, CD45RD, CD18, CD59, CR4, CD45, CD64, and CD44. Further markers of inflammation include alpha.2 macroglobulin receptor, Fibroblast growth factor, Fc gamma R1, Fc gamma R11, CD8, LCA (CD45), CD18, CD59, Apo J, clusterin, type 2 plasminogen activator inhibitor, CD44, Macrophage colony stimulating factor receptor, MRP14, 27E10, 4-hydroxynonenal-protein conjugates, IκB, NFκB, cPLA2, COX-2, Matrix metalloproteinases, Membrane lipid peroxidation, and ATPase activity. HSPC228, EMP1, CDC42, TLE3, SPRY2, p40BBP, HSPC060 and NAB2, or a down-regulation of HSPA1A, HSPA1B, MAPRE2 and OAS1 expression, TACE/ADAM17, alpha-1-Acid Glycoprotein, Angiopoietin-1, MIF, Angiopoietin-2, CD14, beta-Defensin 2, MMP-2, ECF-L/CHI3L3, MMP-7, EGF, MMP-9, EMAP-II, MSP, EN-RAGE, Nitric Oxide, Endothelin-1, Osteoactivin/GPNMB, FPR1, PDGF, FPRL1, Pentraxin 3/TSG-14, FPRL2, Gas6, PLUNC, GM-CSF, RAGE, S100A10, S100A8, S100A9, HIF-1 alpha, Substance P, TFPI, TGF-beta 1, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TLR4, LBP, TREM-1, Leukotriene A4, Hydrolase TSG-6, Lipocalin-1, uPA, M-CSF, and VEGF.”
Wilson et al. (EP3502706A1; published June 26, 2019) discloses sepsis and inflammation biomarkers at para. [0068]: “The at least one further marker and/or parameter of said subject can be selected from the group consisting of a level of lactate, CRP, the sequential organ failure assessment score (SOFA score) of said subject, the simplified acute physiology score (SAPSII) of said subject, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score of said subject and a level of the soluble fms-like tyrosine kinase-1 (sFlt-1), Histone H2A, Histone H2B, Histone H3, Histone H4, calcitonin, Endothelin-1 (ET-1), Arginine Vasopressin (AVP), Atrial Natriuretic Peptide (ANP), Neutrophil Gelatinase-Associated Lipocalin (NGAL), Troponin, Brain Natriuretic Peptide (BNP), C-Reactive Protein (CRP), Pancreatic Stone Protein (PSP), Triggering Receptor Expressed on Myeloid Cells 1 (TREM1), Interleukin-6 (IL-6), Interleukin-1, Interleukin-24 (IL-24), Interleukin-22 (IL-22), Interleukin (IL-20) other ILs, Presepsin (sCD14-ST), Lipopolysaccharide Binding Protein (LBP), Alpha-1-Antitrypsin, Matrix Metalloproteinase 2 (MMP2), Metalloproteinase 2 (MMP8), Matrix Metalloproteinase 9 (MMP9), Matrix Metalloproteinase 7 (MMP7, Placental growth factor (PlGF), Chromogranin A, S100A protein, S100B protein and Tumor Necrosis Factor α (TNFα), Neopterin, , pro-arginine vasopressin (AVP, proAVP or Copeptin), atrial natriuretic peptide (ANP, pro-ANP), E-selectin, ICAM-1, VCAM-1, IP-10, CCL1/TCA3, CCL11, CCL12/MCP-5, CCL13/MCP-4, CCL14, CCL15, CCL16, CCL17/TARC, CCL18, CCL19, CCL2/MCP-1, CCL20, CCL21, CCL22/MDC, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL3L3, CCL4, CCL4L1/LAG-1, CCL5, CCL6, CCL7, CCL8, CCL9, CX3CL1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CXCL2/MIP-2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7/Ppbp, CXCL9, IL8/CXCL8, XCL1, XCL2, FAM19A1, FAM19A2, FAM19A3, FAM19A4, FAM19A5, CLCF1, CNTF, IL11, IL31, IL6, ICAM, Leptin, LIF, OSM, IFNA1, IFNA10, IFNA13, IFNA14, IFNA2, IFNA4, IFNA7, IFNB1, IFNE, IFNG, IFNZ, IFNA8, IFNA5/IFNaG, IFNω/IFNW1, BAFF, 4-1BBL, TNFSF8, CD40LG, CD70, CD95L/CD178, EDA-A1, TNFSF14, LTA/TNFB, LTB, TNFa, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF15, TNFSF4, IL18, IL18BP, IL1A, IL1B, IL1F10, IL1F3/IL1RA, IL1F5, IL1F6, IL1F7, IL1F8, IL1RL2, IL1F9, IL33 or a fragment thereof.”
Conclusion
13. No claim is allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached on M-Th from 7 to 4 EST.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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