Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-3, 7-8, 15, 17, 21, 29-33, and 39 are pending.
Priority
Claims 1-3, 7-8, 15, 17, 21, 29-33, and 39 have priority to PRO 63/532,142 filed on August 11, 2023.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on November 13, 2024, and on November 13, 2024, were filed before the mailing of the First Office Action on July 25, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
Paragraph [0178] Ketanserin image not legible.
Table 2 not legible.
Paragraph [0179] Tegaserod molecular compound image not legible.
Tables 4-6 are not legible.
Paragraph [0189] Brexpiprazde molecular compound image not legible.
Tables 7-16 are not legible.
Appropriate correction is required.
Additionally, it is noted that the listing of references on pages 77-82 in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, “the list may not be incorporated into the specification but must be submitted in a separate paper.” Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 1 is objected to for the following informalities:
Claim 1 recites “a dietary supplement comprising folic acid supplement and/or iron supplement d. a drug that suppresses…” should read “a dietary supplement comprising folic acid supplement and/or iron supplement; d. a drug that suppresses…”.
Claim 1 is further objected to because it includes periods (“.”) at locations other than the end of the claim sentence. MPEP §608.01(m) states “…Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations”. Claim 1 recites the steps “a.”, “b.”, “c.”, “d.”, and “e.”. Appropriate correction is required.
Drawings
The drawings are objected to because:
Figures 4-7 are not legible.
Figures 47-53 are not legible.
Figure 55 is not legible.
Figure 58 is not legible.
Figure 64 is not legible.
Figure 66 is not legible.
Figures 69-70 are not legible.
Figure 73 is not legible.
Figure 82 is not legible.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 7-8, 15, 17, 21, and 29-33 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 it is most nearly connected, to make and/or use the invention:
Nature of the Invention:
The claimed invention is directed to therapeutic methods for preventing or treating severe inflammation, sepsis, and/or septic shock by administering one or more broad classes of pharmacologically distinct compounds. The claims encompass multiple categories of therapeutic agents, including serotonin receptor modulators, receptor tyrosine kinase inhibitors, histamine receptor modulators, dietary supplements, and drugs that increase circulating serotonin levels for the purpose of modulating complex biological pathways involved in systemic inflammatory disease for the purpose of treating or preventing severe inflammation, sepsis, and septic shock. The claims are not limited to any particular infectious etiology and therefore encompass treatment or prevention of inflammation, sepsis, and septic shock arising from bacterial, viral, and/or fungal infections, among other causes.
Breadth of the Claims:
The claim 1 is directed to a method that encompasses methods for preventing or treating severe inflammation, sepsis, and/or septic shock through the administration of broad functional classes of compounds rather than a limited number of specifically identified therapeutic agents. Claim 1 broadly recites drugs that suppress the activity of 5-hydroxytryptamine receptors, receptor tyrosine kinase inhibitors, dietary supplements comprising folic acid and/or iron, drugs that suppress the activity of histamine receptors, and drugs that increase the level of 5-hydroxytryptamine in blood. Claim 32 further broadens the scope of the claimed invention to include methods for treating viral infections where the “severe inflammation” is a result of mutation-prone RNA viruses. Lastly, Claim 33 encompasses methods for treating edema caused by cardiogenic shock, neurogenic shock, and/or anaphylactic shock.
Amount of direction or Guidance in the Specification:
The specification provides limited guidance commensurate with the breadth of the claimed invention. Rather than teaching how to practice the full scope of the claimed therapeutic methods across the numerous recited drug classes, the specification is primarily directed to the development and use of zebrafish lipopolysaccharide (LPS)-induced endotoxicity screening assays for identifying potential therapeutic candidates. Specifically, the specification states “to identify potential therapeutic sepsis therapeutic drugs, a zebrafish endotoxicity/sepsis model was first optimized by evaluating the best combination of endpoints, i.e. mortality, tail edema, and reactive oxygen species production, LPS sources, concentrations, and exposure times to evaluate the potential of the test drugs to provide rescue from sepsis symptoms [¶ 0012]. The specification further teaches that 3-day post fertilization zebrafish embryos and 5-day post fertilization larvae were exposed to 60 µg/mL P. aeruginosa LPS in the presence of 10 µM concentration of each test compound after which mortality and vascular leakage (tail fin edema) were evaluated, with only compounds demonstrating greater than 80% rescue progressing to a second stage screen [¶ 0014]. Of the 644 commercially available compounds screened, only 16 FDA-approved drugs demonstrated excellent rescue in the zebrafish assay, including five compounds that completely rescued mortality and vascular damage [¶ 0015]. The specification further explains that these compounds underwent neurobehavioral testing and additional zebrafish LPS exposure, ultimately concluding that the compounds exhibiting the greatest rescue “are candidates for further evaluation in mammalian sepsis models” [¶ 0016]. Beyond these zebrafish screening studies, the specification provides no additional animal models, mammalian validation studies, or guidance demonstrating that the full scope of the broadly claimed classes of compounds is effective for preventing or treating severe inflammation, sepsis, and/or septic shock. Instead, the disclosure is directed primarily to identifying candidate compounds through an initial zebrafish screening platform rather than providing guidance that enables the full scope of the claimed therapeutic methods.
With respect to claim 32, the specification’s only discussion revolves around the fact that co-administration of certain drugs along with an anti-viral drug “can be contemplated” [¶ 0028]. The only other mention in the specification is related to a generic statement where Applicant states “…onset of sepsis cascade or for treatment of sepsis, and the compounds or composition can be co-administered or in parallel use with antibiotics or other anti-inflammatory drugs, including anti-viral drugs”. Lastly, in paragraph [0155], Applicant briefly discusses the progressive stage of septic shock is very similar to that of other shocks such as cardiogenic shock, neurogenic shock, and anaphylactic shock, in that uncontrolled systemic edema due to increased peripheral vasodilation and vascular permeability leads to a positive feedback of circulatory system collapse. Applicant further states that the compounds and/or compositions can be contemplated. Applicant further states that the claimed drugs can be applied to treatment of severe inflammation caused by virus infection resulting from cytokine storms that are related to specific mutation-prone RNA viruses. However, Applicant provides no definition of what constitutes a mutation-prone RNA virus especially given RNA viruses in general can be characterized as having high mutation rates.
Presence or Absence of Working Examples:
The specification provides working examples limited to a zebrafish LPS-induced endotoxicity screening model. The disclosed examples utilize 3-day post fertilization zebrafish embryos and 5-day post fertilization larvae exposed to LPS derived from P. aeruginosa, E. coli, and K. pneumoniae, wherein mortality, vascular leakage, i.e. tail fin edema, reactive oxygen species production, and neurobehavioral effects were evaluated to identify compounds capable of rescuing zebrafish from LPS-induced endotoxicity [¶ 0012-0016], Figs 1 and 5]. While these examples demonstrate the use of zebrafish screening assay to identify candidate compounds for further investigation, the specification does not provide working examples demonstrating the claimed methods in any mammalian model of severe inflammation, sepsis, or septic shock. Likewise, the specification does not include working examples establishing therapeutic efficacy across broad functional classes of compounds recited in the claims. Instead, the specification expressly concludes that the compounds identified through the zebrafish screen “are candidates for further evaluation in mammalian sepsis models” [¶ 0016], indicating that the disclosed examples represent an initial screening platform for identifying potential therapeutic candidates rather than completed demonstrations of the claimed methods.
Similar to the LPS-induced toxicity, Applicant has provided no working examples of such treatments related to viral infections other than a generic statement that for edema related to cardiogenic shock, neurogenic shock, and anaphylactic shock, the claimed compounds can be contemplated for such treatment, alone or in combination [¶ 0155]. The same lack of working examples also applies to treating viral infections. Applicant provides no examples in vitro or in vivo of these claimed compounds being used to treat infection, sepsis, and/or septic shock as it relates to viral infections.
Relative Skill in the Art:
It is argued that the relative skill in the art, is that of a scientist with several years’ experience in the field, but that the Art itself is a recognition of what is understood by the Artisan, and thus, as seen below, does not make the breadth of the claims more predictable.
The Predictability or Lack thereof in the Art:
The art is unpredictable as it relates to translating therapeutic efficacy observed in zebrafish models to the prevention or treatment of severe inflammation, sepsis, and/or septic shock in mammals. Although zebrafish are recognized as a valuable in vivo model for high throughput drug discovery and phenotypic screening, Cassar et al. explains that false positive and false negative results have been reported, concordance with mammalian studies varies among laboratories, and differences in study design , compound uptake, metabolism, and species, specific mechanisms of action can affect the translatability of zebrafish findings [Use of zebrafish in drug discovery toxicology, Chem Res Toxicol, 2019, Embryo Toxicity ¶ 2]. Cassar et al. further states that zebrafish embryos possess limited intrinsic biotransformation capacity. Furthermore, in-water dosing results in exposure conditions that differ from conventional mammalian dosing routes, and toxicological and pharmacokinetic parameters that include absorption, distribution, metabolism, and excretion, presently, are not able to be correlated to mammalian plasma concentrations [Id.]. Additionally, Cassar et al. recognizes the anatomical, physiological, and regenerative differences between zebrafish and mammals which may also contribute to translational limitation differences between zebrafish results and mammalian disease models. While Cassar et al. does acknowledge that zebrafish are an efficient and valuable model for early-stage compound discovery and prioritization, the authors emphasize that the model possesses inherent limitations with respect to predicting therapeutic efficacy in mammals and is best utilized as part of a broader preclinical evaluation strategy [Id., Abstract]. These considerations are consistent with Applicant’s own disclosure that acknowledges that the biological pathways involved in sepsis and shock are highly interconnected and that “real experiments, at least in vivo model, are the way to decide their applicability for clinical use” [¶ 0215]. The Specification further characterizes the compounds identified through zebrafish screening assays as “candidates for further evaluation in mammalian sepsis models” [¶ 0016]. Accordingly, the art demonstrates that therapeutic efficacy observed in zebrafish screening assays cannot be reliably extrapolated across the full scope of the claimed methods without additional and undue experimentation.
Quantity of experimentation needed:
The claims encompass broad functional classes of pharmacologically diverse compounds for preventing or treating severe inflammation, sepsis, and/or septic shock, while the specification provides experimental support only through zebrafish LPS-induced endotoxicity screening assays. As a result, a person of ordinary skill in the art would need to determine which additional compounds within the broad claimed classes are therapeutically effective, as well as appropriate dosing and efficacy for the claimed disease states. The specification itself acknowledges that the compounds identified in the zebrafish screening assays are candidates for further evaluation and experimentation [¶ 0016], and the further experiments are needed to test their applicability for clinical use [¶ 0215]. Based on this, it would require a person of ordinary skill in the art to engage in undue experimentation. The same analysis is applied to claims 32 and 33 given Applicant has provided no working examples, protocols, or experimental date for either treating a mutation prone RNA virus or edema that results from cardiogenic shock, neurogenic shock, and/or anaphylactic shock. The disclosure is limited to zebrafish models employing bacterial lipopolysaccharides as the inflammatory stimulus. This further reiterates the need for extensive experimentation since a person of ordinary skill would need to identify viral pathogens, viral disease models, make a determination of whether the disclosed compounds are effective against an untold number of potential viruses, optimize dosing regimens, routes of administration, and treatment timing, in order to verify efficacy. This is further exemplified based on the language Based on this, Claims 32 and 33 would also lead a person of ordinary skill in the art to engage in undue experimentation.
Additionally, the specification reports that only 16 compounds out of 466 screened exhibit excellent rescue from sepsis in the zebrafish model [¶ 0015]. However, the claims extend to numerous additional compounds that include 17 different drugs for the 5-HT inhibitor, 1 RTK inhibitor, 12 antihistamines, 7 different SSRIs, and 7 different MAOIs. This results in a total of 44 different claimed compounds. The specification provides no guidance or experimental evidence establishing that all of the listed compounds listed in claims 3, 15, 29, and 30 possess the recited therapeutic activity leading to a person of ordinary skill having to further engage in undue experimentation.
Conclusion:
Based on the above factors, the specification fails to provide sufficient disclosure to allow one of ordinary skill in the art to make and use the claimed invention as it pertains to claims 1-3, 7-8, 15, 17, 21, and 29-33.
Claims 1-3, 7-8, 15, 17, 21, and 29-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 uses the generic phrase of “preventing or treating severe inflammation, sepsis, and/or septic shock” by administrating multiple categories of therapeutic agents, including serotonin receptor modulators, receptor tyrosine kinase inhibitors, histamine receptor modulators, dietary supplements, and drugs that increase circulating serotonin levels for the purpose of modulating complex biological pathways involved in systemic inflammatory disease. The same generic scope is present in each of the dependent claims, i.e. Claims 2-3, 7-8, 15, 17, 21, and 29-33.
The specification provides antecedent basis for “preventing or treating severe inflammation, sepsis, and/or septic shock” as it relates to administering multiple categories of therapeutic agents, including serotonin receptor modulators, receptor tyrosine kinase inhibitors, histamine receptor modulators, dietary supplements, and drugs that increase circulating serotonin levels for the purpose of modulating complex biological pathways involved in systemic inflammatory disease [¶ 0019-0023].
Applicant’s specification describes the disclosed studies as an initial drug discovery and screening platform rather than as completed demonstrations of the full scope of the claimed therapeutic methods. Specifically, Applicant’s specification states that “to identify potential sepsis therapeutic drugs, a zebrafish endotoxicity/sepsis model was first optimized” by evaluating mortality, tail edema, reactive oxygen species production, lipopolysaccharide source, concentration, and exposure times [¶ 0012]. The specification further explained that 644 compounds were screened using 3-day post fertilization zebrafish embryos and 5-day post fertilization zebrafish larvae that resulted in the identification of 16 FDA-approved drugs that demonstrated rescue in the zebrafish model, including five compounds that completely rescued mortality and vascular damage [¶ 0014-0015]. However, the specification characterizes these compounds as merely “candidates for further evaluation in mammalian sepsis models” [¶ 0016]. Additionally, Cassar et al. acknowledges that zebrafish models provide important advantages for high-throughput screening and early-stage drug discovery [Embryo Toxicity ¶ 2]. However, Cassar et al. also explains that zebrafish findings may not always predict mammalian outcomes due to false positives and false negative results due to variability between laboratories, differences in compound uptake, metabolism, species-specific mechanisms of action, and differences in anatomy and physiology [Id]. The authors further note that exposure conditions in zebrafish, including water-dosing, may differ substantially from mammalian administration routes and that zebrafish exposure levels cannot presently be directly correlated with mammalian plasma concentrations [Id.]. Based on this, and the lack of any mammalian animal models, Applicant’s specification does not demonstrate that the selected compounds are capable of functioning in a therapeutic manner as claimed by Applicant and that Applicant has only shown possession of zebrafish LPS-induced endotoxicity assay for screening compounds that can then be further evaluated for potential efficacy. Based on this, a person of ordinary skill would not understand that the claimed compounds were capable of treating or preventing severe inflammation, sepsis, and/or septic shock in a subject in need based on the findings of a zebrafish LPS-induced endotoxicity assay. Additionally, Applicant lists a total of 44 different compounds throughout the claims. However, the specification reports that only 16 compounds out of 466 screened exhibit excellent rescue from sepsis in the zebrafish model [¶ 0015]. However, the claims extend to numerous additional compounds that include 17 different drugs for the 5-HT inhibitor, 1 RTK inhibitor, 12 antihistamines, 7 different SSRIs, and 7 different MAOIs. This results in a total of 44 different claimed compounds. The specification provides no guidance or experimental evidence establishing that all of the listed compounds listed in claims 3, 15, 29, and 30 would lead a person of ordinary skill to understand that applicant is not in possession of the claimed limitations found in these claims. As such, a person of ordinary skill would not understand what starting point would be required for determining what compounds could be used versus what compounds were not considered the 16 selected compounds as stated in the specification in paragraph [0015].
Given the generic scope of “preventing or treating severe inflammation, sepsis, and/or septic shock” by administrating multiple categories of therapeutic agents, including serotonin receptor modulators, receptor tyrosine kinase inhibitors, histamine receptor modulators, dietary supplements, and drugs that increase circulating serotonin levels for the purpose of modulating complex biological pathways involved in systemic inflammatory disease and the absence of teachings of these compounds being administered to treat severe inflammation, sepsis, and/or septic shock in an in vivo model other than a preclinical screening model, i.e. zebrafish, an Artisan would not understand Applicant to be in possession of a method of treating severe inflammation, sepsis, and/or septic shock by administering multiple categories of therapeutic agents, including serotonin receptor modulators, receptor tyrosine kinase inhibitors, histamine receptor modulators, dietary supplements, and drugs that increase circulating serotonin levels for the purpose of modulating complex biological pathways involved in systemic inflammatory disease.
Claim 32 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 32 uses the generic phrase “wherein the severe inflammation is caused by mutation-prone RNA virus infection” as it relates to co-administering the claimed compositions in conjunction with an anti-viral drug to treat infections, sepsis, and/or septic shock related or resulting from mutation-prone RNA viruses.
The specification provides antecedent basis for “wherein the severe inflammation is caused by mutation-prone RNA virus infection” [¶ 0028].
Applicant’s specification states “further, since severe inflammation may occur due to virus infection, in particular due to a mutation-prone RNA virus infection, a method of preventing or treating severe inflammation, comprising co-administering an effective amount of a drug or combination of drugs of the drug disclosed here with an effective amount of at least one anti-viral drug, can be contemplated” [¶ 0028]. In paragraph [0136], Applicant defines the term “RNA virus”. In paragraph [0140], Applicant defines the term “antiviral agent”. And in paragraph [0155], Applicant again states that the claimed drugs can be applied for severe inflammation resulting from mutation-prone RNA viruses resulting in cytokine storms. There is no other mention about referencing RNA viruses and/or severe inflammation resulting from RNA viral infections. The specification does not describe any embodiments directed at viral pathogens. Rather the disclosure is limited to zebrafish models employing bacterial lipopolysaccharide (LPS) from P. aeruginosa, K. pneumonia, and E. coli. As stated in the §112(a) enablement rejection above, there are no phophetic examples, experimental data, or any other description detailing treating sepsis and/or severe inflammation resulting from viral pathogens. MPEP § 2161 states “Specifically, the specification must describe the claimed invention in a manner understandable to a person of ordinary skill in the art in a way that shows that the inventor actually invented the claimed invention at the time of filing. Id.; Ariad, 598 F.3d at 1351, 94 USPQ2d at 1172. The function of the written description requirement is to ensure that the inventor had possession of the specific subject matter later claimed as of the filing date of the application relied on… In re Herschler, 591 F.2d 693, 700-01, 200 USPQ 711, 717 (CCPA 1979), further reiterated in In re Kaslow, 707 F.2d 1366, 217 USPQ 1089 (Fed. Cir. 1983); see also MPEP §§ 2163-2163.04”. Here, Applicant has not shown possession of any compound capable of treating severe inflammation related to mutation-prone RNA viruses other than the general disclosure the physiological mechanics are the similar. Because of this, a person of ordinary skill in the art would not understand Applicant to be in possession of the claimed invention. This is especially true given the numerous mutation-prone RNA viruses that are known to cause infection.
Given the generic phrase “wherein the severe inflammation is caused by mutation-prone RNA virus infection” as it relates to co-administering the claimed compositions in conjunction with an anti-viral drug to treat infections, sepsis, and/or septic shock related or resulting from mutation-prone RNA viruses and the lack of any teachings, an Artisan would not understand Applicant to be in possession of treatment directed viral infections that involve co-administering the claimed compounds and compositions with a anti-viral drug.
Claim 33 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 33 uses the generic phrase “wherein the severe edema is caused by cardiogenic shock, neurogenic shock, or anaphylactic shock” as it relates to treating edema from the list of drugs in recited in the claim.
The specification provides antecedent basis for “wherein the severe edema is caused by cardiogenic shock, neurogenic shock, or anaphylactic shock” [¶ 0029].
Applicant’s specification, similar to claim 32, states that “since severe edema can be caused by cardiogenic shock, neurogenic shock, or anaphylactic shock, a method of treating edema, comprising the step of administering an effective amount of the drug is disclosed here is contemplated” [¶ 0029]. In paragraph [0126], Applicant defines “shock” or “circulatory shock” as a life-threatening condition that occurs when the body is not getting enough blood flow and causes insufficient supply of oxygen and nutrients along with accumulations of acids and toxic substances that leads to damage to cells, tissues, and organs. Applicant then describes cardiogenic shock being related to heart problems as an example, hypovolemic-hemorrhagic shock related to diminished blood flow/volume, anaphylactic shock with an example of histamine mediated allergic reaction, septic shock resulting from infections, neurogenic shock due to a loss of vasomotor tone throughout the body. In paragraph [0155], Applicant again essentially restates paragraph [0029]. And lastly, Applicant, in paragraph [0204] states that the methods described may be applicable to the treatment of systemic edema occurring in cardiogenic, neurogenic, and anaphylactic shock. Similar to claim 32, the specification provides no working examples as it relates to these types of manifested shock. Instead, the disclosure is limited to a zebrafish model typically used for drug screening to determine what drugs may have applicability in the specified treatment where edema was induced following exposure to bacterial lipopolysaccharide. The specification provides no working examples, experimental data, or other description demonstrating treatment of edema resulting from cardiogenic, neurogenic, or anaphylactic shock. MPEP § 2161 states “Specifically, the specification must describe the claimed invention in a manner understandable to a person of ordinary skill in the art in a way that shows that the inventor actually invented the claimed invention at the time of filing. Id.; Ariad, 598 F.3d at 1351, 94 USPQ2d at 1172. The function of the written description requirement is to ensure that the inventor had possession of the specific subject matter later claimed as of the filing date of the application relied on… In re Herschler, 591 F.2d 693, 700-01, 200 USPQ 711, 717 (CCPA 1979), further reiterated in In re Kaslow, 707 F.2d 1366, 217 USPQ 1089 (Fed. Cir. 1983); see also MPEP §§ 2163-2163.04”. Again, Applicant has not provided any evidence other than generic statements that the claimed compounds and/or compositions would be capable of treating edema resulting from the examples as described in the specification. As such, a person of ordinary skill would not understand Applicant to be in possession of the claimed invention.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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 15 and 39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites “pitolisant, and optionally pitolisant”. The claim language is unclear because the same compound is recited as both a required limitation and an optional limitation. Because of this, a person of ordinary skill in the art would not be able to ascertain the metes and bounds of the claimed invention based not knowing whether the claimed limitation is intended or optional.
Claim 39 recites “5-dpf fully developed zebrafish”. However, at 5 days post fertilization, zebrafish are in the larvae stage. The specification further states the 5-dpf zebrafish have more fully developed organ functionality when compared to 3-dpf larvae [¶ 0251]. Given this, a person of ordinary skill would not understand what is meant by “5-dpf fully developed zebrafish” based on the description provided in Applicant’s specification.
Claim 39 recites “directing vascular leakage (tail fin edema)”. As written, the use of parentheses, i.e. (tail fin edema), creates ambiguity as to whether tail fin edema is intended to define vascular leakage or is merely exemplary. Based on this, a person of ordinary skill would not understand the metes and bounds of the claimed invention.
Claim Rejections - 35 USC § 103
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 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.
Claims 1-3, 5, 15, 21, 29, 30, 31, 32, and 39 is rejected under 35 U.S.C. as being unpatentable over Deng et al. [Efficacy and safety of selective serotonin reuptake inhibitors in COVID-19 management: a systematic review and meta-analysis, Clin Microbiol Infect., Jan. 2023], in view of Karakousis et al. [The role of folic acid in SARS-CoV-2 infection: an intriguing linkage under investigation, J. Pers. Med, March 2023], in view of Xiao et al. [Effects of ketanserin on experimental colitis in mice and macrophage function, Int J Mol Med., 2016], in view of Zhao et al. [Suppressive effects of sunitinib on a TLR activation-induced cytokine storm, European Journal of Pharmacology, 2019], in view of Travi [Current status of antihistamine drugs repurposing for infectious diseases, Medicine in Drug Discovery, September 2022], in view of Szalek et al. [Sunitinib in combination with clarithromycin or azithromycin-is there a risk of interaction or not?, Pharmacological Reports, 2012], in view of Ostadkarampour and Putnins (Hereinafter Putnins) [Monoamine oxidase inhibitors: a review of their anti-inflammatory therapeutic potential and mechanisms of action, Frontiers in Pharmacology, 2021], in view of Philip et al. [Development of a zebrafish sepsis model for high-throughput drug discovery, Molecular Medicine, 2017], in view of Pier [Pseudomonas aeruginosa lipopolysaccharide: a major virulence factor, initiator of inflammation and target for effective immunity, International Journal of Medical Microbiology, 2007].
For claim 1 where a method for preventing and/or treating severe inflammation, sepsis, and/or septic shock that involves administering a SSRI, Deng et al., researching the data related to fluvoxamine with reduced hospitalization of COVID-19, found that medium doses of Fluvoxamine led to reduced hospitalization [Hospitalization and emergency room visits].
Additionally, Karakousis et al. teaches discloses that vitamin definiciency increases host susceptibility and that folic acid could be considered a potential inhibitor for SARS-CoV-2 virus entry into host cells and viral replication, as well as binding at essential residues [5. Conclusion].
For the claim 1 limitation where a drug that suppresses the activity of 5-HT, Xiao et al. teaches that ketanserin has been shown to exert anti-inflammatory effects [Abstract].
Claims 2 and 3 are also rejected under the same analysis applied to the claim 1’s limitation where the drug administered suppresses the activity of 5-HT.
For the claim 1 limitation that involves administering a drug that inhibits the activity of receptor tyrosine kinases, Zhao et al. teaches that sunitinib, a tyrosine kinase inhibitor, could depress SZU101-induced IL-6 production in a concentration-dependent manner, as well as exerting inhibitory effects on the growth of RAW 264.7 murine macrophage cells [3.1 In vitro cytokine release after combined administration of TKIs and a TLR7 agonist]. Zhao et al. also confirmed that sunitinib was able to inhibit cytokine production [3.2 In vitro cytokine release after combined administration of sunitinib and TLR agonists].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Deng et al. that discusses the potential anti-inflammatory effect provided by Fluvoxamine, a SSRI, in the treatment in COVID-19, or the use of folic acid as described in the article by Karakousis et al., or treating severe inflammation where a protective role was shown in cases where FA deficiency existed, or the use of ketanserin as an anti-inflammatory based on Xiao et al. teachings where studies have shown such properties independent of the baroreflex, or Zhao et al. teaching that sunitinib is capable of inhibiting cytokine production to treat inflammation. In light of these disclosures discussing the disclosed compounds may be useful in treating inflammation, the disclosures presented are not speculation and provide a scientific basis for the proposed use by describing the compounds anti-inflammatory activity. In view of this, a person of ordinary skill in the art would have a reasonable expectation that the disclosed compounds are capable of exhibiting a therapeutic benefit in the presence of inflammation including severe inflammation.
Claim 5 is also rejected under Zhao et al. for the same rationale as discussed in the claim 1 limitation for administering a drug that inhibits the activity of receptor tyrosine kinase.
For claim 15 where the antihistamine includes a Markush listing, Travi teaches cetirizine were associated with a significant decrease in incidence of SARS-CoV-2 [5.1 SARS-coV-2 ¶ 4].
For claim 21, the same analysis applied to claim 1 for the administration of a RTK is applied here.
For claim 29, the same analysis applied to the limitation of administering an SSRI is applied here given Deng et al. discloses fluvoxamine as the compound being studied.
For claim 30 where the MAOI comprises a Markush listing, Putnins lists numerous MAOI’s that are included with potential uses as an anti-inflammatory such as isocarboxazid, phenlzine, tranylcypromine, rasagiline, moclobemide and iproniazid [Table 1].
For claim 31 where antibiotics are co-administered with certain claimed compounds, Szalek et al. discloses there are no significant effect of co-administration of clarithromycin or azithromycin on the pharmacokinetics of sunitinib that was found in rabbits [Conclusion].
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Deng et al. that discusses the potential anti-inflammatory effect provided by Fluvoxamine, a SSRI, in the treatment in COVID-19, or the use of folic acid as described in the article by Karakousis et al., or treating severe inflammation where a protective role was shown in cases where FA deficiency existed, or the use of ketanserin as an anti-inflammatory based on Xiao et al. teachings where studies have shown such properties independent of the baroreflex, or Zhao et al. teaching that sunitinib is capable of inhibiting cytokine production. In light of these disclosures discussing the disclosed compounds may be useful in treating inflammation, the disclosures presented are not speculation and provide a scientific basis for the proposed use by describing the compounds anti-inflammatory activity. In view of this, a person of ordinary skill in the art would have a reasonable expectation that the disclosed compounds are capable of exhibiting a therapeutic benefit in the presence of inflammation including severe inflammation.
For claim 39, Philip teaches a zebrafish model developed specifically for high-throughput drug discovery for sepsis [Abstract], use of 3 day post fertilization zebrafish [Measuring activation of immune cells and ROS production], use of LPS-induced zebrafish endotoxemia/sepsis models [Abstract], identifies tail fin edema resulting from vascular leakage [Validating the utility of the zebrafish sepsis model for high-throughput drug screening applications ¶ 2], uses vascular leakage as a primary readout [Id.], uses ROS production as a primary readout [Id.], screens compounds and identifies agents that rescue LPS-induced phenotypes [Abstract]. In addition, Philip et al. teaches that larvae 3-dpf were exposed to LPS by immersion technique where the larvae were treated with 25, 50, 75, 100, and 200 µg/mL of LPS derived from E. coli [LPS-induced zebrafish sepsis model: survival curve and phenotype analysis]. Furthermore, the 3-dpf zebrafish larvae were exposed via static immersion for periods up to 24 hours [Id.]. Philip et al. also discloses the purpose of the zebrafish model is to identify drugs capable of treating inflammation and/or sepsis, including circulatory shock, as potential candidates for use in treating said conditions [Discussion ¶ 1]. However, Philip et al. does not teach the use of P. aeruginosa as the source of the LPS.
For this limitation, Pier teaches that P. aeruginosa LPS was a well-characterized virulence factor and a known initiator of inflammatory responses prior to the filing date. Specifically, Pier describes P. aeruginosa LPS as a major component responsible for initiating host inflammatory responses and contributing to bacterial pathogenicity [Abstract]. Given this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Philip et al. that describes a zebrafish sepsis model used for high-throughput drug discovery where LPS, sourced from E. coli, was used for endotoxin-induced inflammation and injury with the additional teachings of Pier that disclosed that P. aeruginosa is a well-known inducer of inflammation. Based on this, there would have a been a reasonable expectation of success that a person of ordinary skill would have combined the teachings of Philip et al. with the additional teachings of Pier where the skilled artisan would have substituted the sourced E. coli LPS with sourced P. aeruginosa LPS in order to induce a sepsis-like phenotype in zebrafish model based off of P. aeruginosa and would then further be used in analyzing drugs in order to determine potential effectiveness in inflammation, sepsis, and/or circulatory shock.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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