DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 1-18, 20, and 25 are pending.
Preliminary Amendment(s)
Applicant’s preliminary amendment filed on 08/22/2023 is acknowledged. The specification was amended to add a statement of related applications.
Applicant’s preliminary amendment filed on 01/08/2024 is acknowledged. The claims were amended to cancel claims 19, 21-24, and 26-38. Claims 3, 4, 6, 7, 9, 12, 13, 14, 16, 17, 20, and 25 were amended to remove multiple dependencies.
Priority
This application is a 371 of PCT/US2022/017274 filed 02/22/2022. Acknowledgement is made of Applicant’s claim for priority based on a provisional application filed as 63/151,858 on 02/22/2021.
All claims are given the priority date of 02/22/2021.
Information Disclosure Statement
Receipt of information disclosure statement, filed on 05/28/2024 is acknowledged.
Drawings
The drawings are objected to because:
X and/or Y-axes are illegible for the following:
FIG. 1C;
FIG. 2A (micrograph);
FIG. 4A-B;
All graphs in FIG. 7;
Each graph in FIG. 10A; and
All graphs in FIG. 11.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
Under Background:
Page 1, line 28 recites, “Most people diagnosed with COVOD-19 do not require…”. It would be remedial to amend “COVOD-19” to recite “COVID-19”.
Under Brief Description of the Drawings:
Figure 3 recites “shown in orange diamonds” in lines 30-31 of page 5. It would be remedial to amend this to recite “shown in diamonds”, to remove the color indication.
Figure 3 recites “(light blue curve) … (dark blue curve)” in line 13 of page 6. It would be remedial to amend this to recite “(grey curve) … (black curve)” to remove the color indication.
Figure 6 recites “…with blue to red representing low to high values of each index, and the color intensity representing the magnitude of value…. Missing values are shown in grey.”, in line 30 of page 6 and line 2 of page 7. It would be remedial to amend this to remove color indication.
Appropriate correction is required.
The use of the term(s):
Lipidomix (page 16, line 17), (page 17, line 11);
Hypersil Gold (page 16, line 23);
Exploris (orbitrap) (page 16, line 26);
Poroshell (page 17, line 12);
Somalogic (page 27, line 6);
Somascan (page 27, line 11);
which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 5 is objected to because of the following informalities: “…secreted phospholipase A2 isoform IIA (sPLA2-IIA) …”. The 2 in sPLA2 is subscript, but that is the only place in any of the claims where the 2 for isoform 2 is subscript. For consistency, it would be remedial to amend to recite “…secreted phospholipase A2 isoform IIA (sPLA2-IIA) …” or change all other claims which contain sPLA2 to sPLA2.
Claim 11 is objected to because of the following informalities: “…wherein said subject has PASC.” It would be remedial to spell out PASC, as it is not a well-known acronym. Claim 15 is objected to because of the following informalities: “…administering an sPLA2inhibitor to said subject…”. It would be remedial to add a space between sPLA2 and inhibitor.
Claim 25 is objected to because of the following informalities: line 2 recites "… said patient". Claim 25 is dependent upon claim 1, which does not recite “patient” in the claim, but recites “subject”. It would be remedial to amend claim 25 to recite “said subject”.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim(s) 1-16, 20, and 25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 2A: Prong One
The independent claim(s) recites “…when said sample has an elevated level of sPLA2” (of independent claim(s) 1 and 15), and “…when said sample has an elevated level of sPLA2-IIA” (of independent claim 5).” The claim recites the step of comparing collected information to a predefined threshold, which is an act of evaluating information that can be practically performed in the human mind. Thus, this step is an abstract idea in the "mental process" grouping.
Dependent claim 20 further limits the judicial exception, i.e., wherein said elevated level of sPLA2 is an elevated level relative to a reference level selected from the group consisting of the level in a subject not diagnosed with a respiratory disorder, the level of said subject prior to being diagnosed with said respiratory disorder, and a population average of subject not diagnosed with respiratory disorders. However, this limitation in an abstract idea in the “mathematical concepts” grouping reading on a mathematical relationship. It is important to note that a mathematical concept need not be expressed in mathematical symbols, because "[w]ords used in a claim operating on data to solve a problem can serve the same purpose as a formula." In re Grams, 888 F.2d 835, 837 and n.1, 12 USPQ2d 1824, 1826 and n.1 (Fed. Cir. 1989). See Digitech Image Techs., LLC v. Elecs. for Imaging, Inc., 758 F.3d 1344, 1350, 111 USPQ2d 1717, 1721 (Fed. Cir. 2014) (holding that claims to a ‘‘process of organizing information through mathematical correlations’’ are directed to an abstract idea (see MPEP 2106.04(a)(2) IA).
Step 2A: Prong Two
The judicial exception is not integrated into a practical application. The independent claims as a whole, looking at the additional elements individually and in combination, does not integrate the judicial exception into a practical application.
The independent claim(s) recite the additional limitation(s) of (1) “a) assaying a sample from said subject for the level of a secreted phospholipase A2 (sPLA2) (or sPLA2-IIA) …”, and (2), “… b) administering an sPLA2 (or sPLA2-IIA) inhibitor to said subject when said sample has an elevated level of sPLA2 (or SPLA2-IIA).” Regarding limitation (1), this limitation is considered insignificant extra-solution activity. Mere data gathering in conjunction with a judicial exception (i.e., abstract idea) does not add a meaningful limitation to the process, see Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. Regarding limitation (2), this limitation reads on an embodiment where nothing happens if the sample does not have an “elevated” level of sPLA2 (or sPLA2-IIA). Further, combining the two limitations of claim(s) 1, 5, or 15 tells the relevant audience (doctors) about the abstract idea and at most adds a suggestion that the doctors take that abstract idea into account when treating their patients/subjects. Thus, rendering the combination of the limitations as merely indicating a field of use/technological environment. Accordingly, the limitation(s) fail to meaningfully limit the independent claim(s) because it/they does/do not require any particular application of the recited abstract idea.
Dependent claim(s) 2-4 further limit the sPLA2 of the assaying step: a low MW, Ca++ dependent sPLA2 (of claim 2); wherein said sPLA2 is SPLA2-IIA (of claim 3); and wherein the sPLA2 is selected from the group consisting of… (of claim 4). However, these limitations are considered post-solution activity, i.e., selecting the type of data of the insignificant extra-solution activity, and does not impose meaningful limitations on the process in regard to a practical application.
Dependent claim(s) 6-13 and 25 further limit the patient population to be assayed: wherein said condition, disease or disorder is or includes multiple organ failure (of claim 6), wherein said condition, disease or disorder is selected from the group consisting of… (of claim 7), wherein said respiratory disorder is acute respiratory distress syndrome (ARDS) (of claim 8), wherein said subject is infected with or has been infected with the SARS-CoV-2 virus (of claim 9), wherein said subject has one or more symptoms of COVID-19 (of claim 10), wherein said subject has PASC (of claim 11), wherein said subject is at increased risk of severe disease or death from said condition, disease or disorder (of claim 12), wherein said subject is over the age of 65 (of claim 13), and wherein said patient has a blood urea nitrogen (BUN) level greater than or equal to 16 mg/dl (of claim 25). However, these limitations are considered a pre-solution activity, i.e. selecting a particular data source, and do no impose meaningful limitations on the process in regard to a practical application.
Dependent claim 14 further limits dependent claim 1 as a whole, i.e., further comprising assaying one or more of the subject’s respiration rate, oxygen saturation or pulmonary lesion progression. However, this limitation is extra-solution activity in addition to assaying sPLA2 and will be further analyzed in Step 2B for whether or not this limitation is sufficient to amount to significantly more than the judicial exception.
Dependent claim 16, further limits the assaying step, i.e., wherein said assaying comprises an immunoassay. However, this limitation is extra-solution active that limits the type of assay to be performed and will be further analyzed in Step 2B for whether or not this limitation is sufficient to amount to significantly more than the judicial exception.
Step 2B
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As mentioned in Step 2A: Prong Two, the independent claim(s) recite the additional limitation(s) of (1) “a) assaying a sample from said subject for the level of a secreted phospholipase A2 (sPLA2) (or sPLA2-IIA) …”, and (2), “… b) administering an sPLA2 (or sPLA2-IIA) inhibitor to said subject when said sample has an elevated level of sPLA2 (or sPLA2-IIA).” Not only is limitation (1) insignificant extra-solution activity, it is also well-known, routine, and conventional in the art, and thus does not add a meaningful additional claim element. Cayman Chemical (sPLA2 (human Type IIA) ELISA Kit, Cayman Chemical, Item No. 501380, published October 6th, 2022) discloses an sPLA2 assay (human type IIA) ELISA kit. Specifically, “Cayman’s sPLA2 (human Type IIA) ELISA kit is a sandwich assay that can be used for the quantification of sPLA2 in plasma, synovial fluid, and other sample matrices. The ELISA kit has a range from 31.3-2,000 pg/ml, with a limit of quantification of 31.3 pg/ml.”, (see page 6, About This Assay). Regarding limitation (2), as specified above, this limitation reads on an embodiment where nothing happens if the sample does not have an “elevated” level of sPLA2 (or sPLA2-IIA). Further, combining the two limitations of claim 1, 5, or 15, tells the relevant audience (doctors) about the abstract idea and at most adds a suggestion that the doctors take that abstract idea into account when treating their patients/subjects. Thus, rendering the combination of the limitations as merely indicating a field of use/technological environment, and failing to add meaningful additional claim elements.
Dependent claim(s) 2-3, recited above in Step 2A: Prong Two, further limit the sPLA2 of the assaying step, but do not meaningfully limit claim 1. These limitations are considered post-solution activity, i.e., selecting the type of data of the insignificant extra-solution activity, and are also well-known, routine, and conventional in the art as disclosed by Cayman Chemical above. Thus, the limitations of dependent claim(s) 2-3 do not add a meaningful additional claim element.
Dependent claim 4, recited above in Step 2A: Prong Two, further limits the sPLA2 of the assaying step, but does not meaningfully limit claim 1. This limitation is considered post-solution activity, i.e., selecting the type of data of the insignificant extra-solution activity, and is also well-known, routine, and conventional in the art as disclosed by MyBioSource (MBS2020295 96 Tests, ELISA Kit For Phospholipase A2, Group XIIB (PLA2G12B), Instruction Manual, 11th edition, Published July 2013). MyBioSource discloses, “The kit is a sandwich enzyme immunoassay for in vitro quantitative measurement of PLA2G12B in human serum, plasma, tissue homogenates and other biological fluids.”, (see page 1). Thus, the limitation of dependent claim 4 does not add a meaningful additional claim element.
Dependent claim(s) 6-13 and 25, recited above in Step 2A: Prong Two, further limit the patient population to be assayed. These limitations are considered a pre-solution activity, i.e. selecting a particular data source, and do no impose meaningful limitations on the process. The limitations recited in the claims above do not meaningfully limit the claim because it is unclear whether sPLA2 would be elevated in any of the patient/subject populations the limitations apply to. Further, there is an embodiment where those limited patient populations are assayed and sPLA2 (or sPLA2-IIA) is not elevated, resulting in no additional meaningfully element that would trigger the administration of the sPLA2 (or sPLA2-IIA) inhibitor.
Dependent claim 14, recited above in Step 2A: Prong Two, further limits claim 1 as a whole, and adds the additional step of measuring respiration rate, oxygen saturation or pulmonary lesion progression. However, this limitation is extra-solution activity that is well known, routine, and conventional. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps discussed above are routinely used by those of ordinary skill in the art. “Assaying” from a “subject” respiration rate is well-understood, routine, and conventional activity in the art for diseases or disorders, such as acute respiratory distress syndrome (ARDS) as disclosed by
De Luca et al (Secretory phospholipase A2 pathway during pediatric acute respiratory distress syndrome: A preliminary study, Pediatr Crit Care Med, Vol 12, Issue 1, Pages 1-5, Published January of 2011):
“Objective: To verify if secretory phospholipase A2 (sPLA2) is increased in pediatric acute respiratory distress syndrome (ARDS) triggered or not by respiratory syncytial virus infection and to clarify how the enzyme may influence the disease severity and the degree of ventilatory support… Measurements and Main Results: We enrolled six respiratory syncytial virus-ARDS babies, five ARDS babies, and six control infants. The sPLA2 activity and tumor necrosis factor (TNF) were significantly higher in the bronchoalveolar lavage of ARDS infants. Worst oxygenation, ventilation, and longer pediatric in tensive care unit stay and ventilation time were present in ARDS babies. No differences were found in Clara cell secretory protein and in serum cytokines levels. Because there is no correlation between bronchoalveolar lavage protein content (a marker of permeability) and sPLA2, the enzyme seems mainly produced in the alveoli. TNF-, the main inductor of sPLA2 expression, significantly correlates with the enzyme level in the bronchoalveolar lavage. Significant positive correlations exist between sPLA2, TNF-and oxygen need, mean airway pressure, ventilatory index, and the Murray’s lung injury score.”, (see page 1, column 1 paragraph 1 and 6 to column 2 paragraph 1).
Further, De Luca et al discloses:
“All infants were ventilated through cuffed tubes, with Servo-I ventilator (Maquet Critical Care, Solna, Sweden) providing assisted-pressure controlled ventilation and allowing 6 mL/kg of tidal volume. Single breath static respiratory system compliance was measured during a passive exhalation, after a 300-msec end-inspiratory occlusion (14). Mean airway pressure, FIO2, PaO2/FIO2 were recorded just before the BAL; and ventilatory index was calculated as follows: (respiratory rate X [peak pressure expiratory pressure] positive end PaCO2/1000). Oxygenation index was also calculated, at the study entry, as follows: (Mean Airway Pressure FIO2/PaO2). Severity of ARDS was assessed using “Murray’s lung injury score modified for children” at the ARDS diagnosis (18).”, (see page 2, column 2, paragraph 1).
Dependent claim 16, as recited above in Step 2A: Prong Two, further limits the assaying step to a particular assay. However, this limitation is extra-solution activity that is well known, routine, and conventional in the art. Cayman Chemical discloses the use of immunoassay for measuring sPLA2, particularly sPLA2-IIA.
Thus, the additional elements do not add significantly more. The claim(s) as a whole does/do not amount to significantly more than a judicial exception.
Accordingly, claim(s) 1-16, 20, and 25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
One way to overcome the judicial exception of claim 1 would be to (1) incorporate the non-rejected dependent claim(s) into claim 1, and (2) include an additional step that highlights the practical applications such as the following recitation:
A method of treating COVID-19 in a subject, comprising: a) assaying a sample from said subject for the level of secreted phospholipase A2-IIA (sPLA2-IIA); b) identifying said subject as having an elevated level of sPLA2-IIA relative to a population average of non-Covid 19 subjects; and c) administering LY315920 to said identified subject.
Claim Rejections - 35 USC § 112 (Written Description)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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.
Claim(s) 1-18, 20, and 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, Applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
Claim 1 is drawn to a genus of “sPLA2 inhibitor” for the treatment of a condition, disease or disorder when a sample (from a subject) has an elevated level of sPLA2. The rejected claim thus comprises a genus of “sPLA2 inhibitor” and is defined as belonging to the broad class of “inhibitors” and as having the function of treating a condition, disease or disorder when a sample (from a subject) has an elevated level of sPLA2.
Claim 17 (dependent on claim 1) limits the “sPLA2 inhibitor” to an sPLA2 inhibitor selected from the group consisting of a nucleic acid, an antibody, and a small molecule. Accordingly, claim 17 is drawn to a subgenus defined by nucleic acid, an antibody, and a small molecule that must have the function of treating a condition, disease or disorder when a sample (from a subject) has an elevated level of sPLA2.
Claim 18 (dependent on claim 17) limits the “sPLA2 inhibitor” to a sPLA2 inhibitor that is a small molecule, wherein said small molecule is selected from the group consisting of varespladib methyl, AZD2716, 7,7-Dimethyleicosadienoic Acid (DEDA), oleyloxyethyl phosphorylcholine, luffariellolide, thioetheramide PC, 4-[(1-oxo-7- phenylheptyl)amino]-(4R)-octanoic acid, LY315920, and yS-[(1-oxo-7-phenylheptyl)amino]- 4-(phenylmethoxy)-benzenepentanoic acid. Accordingly, claim 18 is drawn to species of the subgenus, defined by the small molecules listed above, that must have the function of treating a condition, disease or disorder when a sample (from a subject) has an elevated level of sPLA2.
Claim 5 is drawn to a genus of “sPLA2-IIA inhibitor” for the treatment of a condition, disease or disorder when a sample (from a subject) has an elevated level of sPLA2-IIA. The rejected claim thus comprises a genus of “sPLA2-IIA inhibitor” and is defined as belonging to the broad class of “inhibitors” and as having the function of treating a condition, disease or disorder when a sample (from a subject) has an elevated level of sPLA2-IIA.
Claim 15 is drawn to a genus of “sPLA2 inhibitor” for the treatment of COVID-19 when a sample (from a subject) has an elevated level of sPLA2. The rejected claim thus comprises a genus of “sPLA2 inhibitor” and is defined as belonging to the broad class of “inhibitors” and as having the function of treating COVID-19 when a sample (from a subject) has an elevated level of sPLA2.
To satisfy the written description requirement, MPEP §2163 states, in part “… a patent
specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species by “… disclosure of relevant, identifying characteristics, i.e.,
structure or other physical and/or chemical properties, by functional characteristics coupled with
a known or disclosed correlation between functional and structure, or by a combination of such
identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.”
The specification envisions the sPLA2/sPLA2-IIA inhibitor as the following:
“Any suitable sPLA2 (e.g., sPLA2-IIA) inhibitor may be utilized in the methods described herein. Examples include but are not limited to, antibodies, nucleic acids (e.g., antisense nucleic acids, siRNAs, shRNAs, miRNAs, etc.), and small molecules (e.g., varespladib methyl, AZD2716, 7,7-Dimethyleicosadienoic Acid (DEDA), oleyloxyethyl phosphorylcholine, luffariellolide, thioetheramide PC, 4-[(1-oxo-7-phenylheptyl)amino]-(4R)-octanoic acid, LY315920, oryS-[(1-oxo-7-phenylheptyl)amino]-4-(phenylmethoxy)-benzenepentanoic acid).”, (see page 3, paragraph 3).
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims in regard to structure and function, the examples are representative of (a) broad subgenus’ of “inhibitor” such as antibodies, nucleic acids, and small molecules, and (b) broad species within the subgenus of nucleic acids, such as antisense nucleic acids, siRNAs, shRNAs, miRNAs, and (c) defined species of small molecules such as varespladib methyl, AZD2716, 7,7-Dimethyleicosadienoic Acid (DEDA), oleyloxyethyl phosphorylcholine, luffariellolide, thioetheramide PC, 4-[(1-oxo-7-phenylheptyl)amino]-(4R)-octanoic acid, LY315920, oryS-[(1-oxo-7-phenylheptyl)amino]-4-(phenylmethoxy)-benzenepentanoic acid), all well-known sPLA2/sPLA2-IIA inhibitors. All of the examples described in the specification must have the function of treating a condition, disease or disorder (or COVID-19) when said sample (from the subject) has an elevated level of sPLA2/sPLA2-IIA. These results are not necessarily predictive of all “sPLA2/sPLA2-IIA inhibitors” that must be capable of treating a condition, disease or disorder (or COVID-19) when said sample (from the subject) has an elevated level of sPLA2/sPLA2-IIA. Thus, it is impossible for one to extrapolate from these examples of antibody, nucleic acid, and small molecules described herein that the genus sPLA2/sPLA2-IIA inhibitors would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of “sPLA2/sPLA2-IIA inhibitors” capable of treating a condition, disease or disorder (or COVID-19) when said sample (from the subject) has an elevated level of sPLA2.
Looking to a review article on sPLA2/sPLA2-IIA inhibitors, Dennis et al (Phospholipase A2 Enzymes: Physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention, Chem Rev, Volume 111, pages 6130-6185, published September 12th, 2011) describes sPLA2/sPLA2-IIA inhibitor structure:
Dennis et al discloses various types of inhibitors for sPLA2/sPLA2-IIA.
“The early attempts to develop PLA2 inhibitors were focused on phospholipid analogues and started in earnest in the 1980s. 1-Stearyl-2-stearoylaminodeoxy phosphatidylcholine (1) was studied and found to be a reversible inhibitor of PLA2 from cobra venom (Naja naja naja). At the same time, a series of long-chain difluoroketones was studied. Derivative 2b based on phosphatidylethanolamine was the most active in this series against cobra venom PLA2. Phospholipid analogues (3) containing a phosphonate group in place of the ester at the sn-2 position of the glycerol backbone were found to be tight-binding inhibitors of the same enzyme. A series of structurally modified phospholipids were used to delineate the structural features involved in the interaction between cobra venom PLA2 and its substrate. A very potent inhibitor (thioether amide PE, 4) was identified among them. At the same time, a class of acylamino analogues of phospholipids (5) was developed and studied as inhibitors of
PNG
media_image1.png
136
520
media_image1.png
Greyscale
porcine pancreatic PLA2.”, (see page 6139, column 1).
PNG
media_image2.png
322
552
media_image2.png
Greyscale
PNG
media_image3.png
154
318
media_image3.png
Greyscale
“The substrate specificity at the active site of recombinant human synovial fluid PLA2 was investigated by using a series of short-chain phospholipid analogues such as 8.”, (see page 6139, column 2, paragraph 2).
“In 1992, Bristol-Myers Squibb presented the dicarboxylic acid 9a (BMS-181162) as the first specific inhibitor of a 14 kDa PLA2 (specificly compared to other types of phospholipases, PLC, PLD, and PLA1)… A similar derivative, BMS-188184, presented better stability and activ ity as a backupagentforBMS-181162inclinicalstudies.BMS 181162 reached phase II clinical trials as a cream for topical application for the treatment of psoriasis, but the results were disapointing as the drug could not penetrate beyond the outer layer of the skin… The mechanism of inhibition of GIIA sPLA2 (referred to by the authors as human nonpancreatic sPLA2) by the anti-inflammatory agent BMS-181162 was studied.132c BMS-181162 inhibited human platelet PLA2 with an IC50 =40μM, and it was able to reduce mouse ear edema with an ED50 = 160 μg/ear in a phorbol-ester induced acute inflammation assay, whereas BMS 188184inhibited human platelet PLA2withanIC50=17μMand reduced mouse ear edema with an ED50 = 9.37 μg/ear.132d It is unclear whether the inhibition observed in the mouse ear edema model reflected inhibition of just GIIA sPLA2 or other PLA2s as well.”, (see page 6139, column 2, paragraphs 3 and 4).
“Among a series of biaryl diacid inhibitors of human sPLA2, biarylacetic acid derivatives were found to be more active than biaryl acids or biarylpropanoic acids.133 Compounds with larger hydrophobic groups were usually more potent inhi bitors of the enzyme. Compounds 10a and 10b were found to possess significant anti-inflammatory activity in a phorbol ester-induced mouse ear edema model of chronic inflammation… Through computer-assisted methods, Roche developed the very potent inhibitor 11 containing the iminodiacetic acid group (IC50 = 0.23 μM for human synovial fluid PLA2).134 Inhibitor 11 exhibited anti-inflammatory activity in two separate animal models of inflammation.”, (page 6139, column 2, paragraph 5 to page 6140, column 2, paraphs 1 and 2).
PNG
media_image4.png
192
496
media_image4.png
Greyscale
PNG
media_image5.png
186
332
media_image5.png
Greyscale
PNG
media_image6.png
210
296
media_image6.png
Greyscale
Dennis et al goes on to describe primary amides, acylamino phospholipid analogues, nonphospholipid amides, amides derived from D-tyrosine, and indoles as sPLA2 inhibitors. Further, on page 6142 Dennis et al describes LY333013 (methyl verespladib), on page 6143 Me-Indoxam, and on page 6144 oxadiazolones (PMS815, PMS1062). Dennis et al describes Aptamers and peptides (PIP-18) on page 6145, as well as natural products (Manoalide, Petrosaspongiolide M, Scalaradial, Thielocin B3, YM-26567, and YM-26734).
Looking to a patent publication on sPLA2/sPLA2-IIA inhibitors, Kawauchi et al (WO 9620959 A1, published July 11th, 1996; translation of the specification provided under NPL) describes sPLA2/sPLA2-IIA inhibitor structure in regard to antibodies:
“The present invention includes the following. (1) A monoclonal antibody capable of inhibiting the activity of human-derived type II phospholipase A2 and inhibiting the activity of monkey-derived type II phospholipase A2 and mouse or mouse-derived type II phospholipase A2, or a part thereof, Protein with function. (2) A monoclonal antibody having an action of releasing type II phospholipase A2 bound to a cell membrane, or a protein having the action including a part thereof. (3) The monoclonal antibody or protein according to (2), wherein the phospholipase A2 is derived from human. (4) It can inhibit the activity of human-derived type II phospholipase A2 and inhibit the activity of monkey-derived type II phospholipase A2 and Z or mouse-derived type II phospholipase A2, and can bind to cell membrane type II phospholipase A2 Or a protein comprising a part thereof and having said action.”, (see page 4, paragraphs 7 to 11).
Kawauchi et al provides the sequence of the variable region of the light chain in Fig. 10, and the variable region of the heavy chain in Fig. 11. Kawauchi et al further describes on page 1 in paragraph 4, “For phospholipase A2, types such as type I, type II, intracellular and the like are known (Heikei et al., Japan clinical, 1994 special issue, 202-206). Among them, type I phospholipase A 2 is induced in the inflamed region of inflammation accompanied with inflammatory reaction, and a large amount of enzyme is released into the blood. Furthermore, there are various reports suggesting that this enzyme is part of the exacerbation of the disease state or a part of its cause in various inflammatory diseases.”
Looking to a patent publication on sPLA2/sPLA2-IIA inhibitors, Bennett et al (US 2005/0143331) describes sPLA2/sPLA2-IIA inhibitor structure:
“Antisense compounds, compositions and methods are provided for modulating the expression of Phospholipase A2, group IIA (synovial). The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Phospholipase A2, group IIA (synovial). Methods of using these compounds for modulation of Phospholipase A2, group IIA (synovial) expression and for treatment of diseases associated with expression of Phospholipase A2, group IIA (synovial) are provided.”, (see abstract).
Bennett et al discloses sequences targeting the 5’ UTR, coding region, 3’UTR, and introns of sPLA2-IIA in table 2 starting on page 28.
Further, Bennet et al disclose at paragraph [0007], “Synovial phospholipase A2 (PLA2 group IIA) may act as an acute phase protein which enhances inflammation and tissue damage (Pruzanski et al., J. Lipid Res., 1998, 39, 2150-2160) and upregulation is observed in inflammatory disorders such as rheumatoid arthritis (Bidgood et al., J. Immunol., 2000, 165, 2790-2797; Lin et al., J. Rheumatol., 1996, 23, 1162-1166), osteoarthritis (Jamal et al., Ann. Rheum. Dis., 1998, 57, 550-558), systemic lupus erythematosus (Pruzanski et al., J. Rheumatol., 1994, 21, 252-257), Crohn's disease (Lilja et al., Clin. Chem. Lab Med., 2000, 38, 1231-1236), chronic proliferative cholangitis (Shoda et al., Hepatology, 1999, 29, 1026-1036), inflammatory bowel disease (Minami et al., Am. J. Gastroenterol., 1993, 88, 1076-1080; Minami et al., Gut, 1994, 35, 1593-1598), glomerulonephritis (Wada et al., Kidney Int., 1997, 52, 934-941), septic shock and multiple organ failure (Vadas et al., J. Lipid Mediat., 1993, 8, 1-30), endotoxic shock (Yokota et al., Biochim. Biophys. Acta, 1999, 1438, 213-222), psoriasis (Vadas et al., J. Lipid Mediat., 1993, 8, 1-30), acute pancreatitis (Nevalainen, Clin. Chem., 1993, 39, 2453-2459), cholesterol stones resulting from gallbladder inflammation (Kano et al., Hepatology, 1998, 28, 302-313) and preterm labor resulting from intrauterine inflammation (Koyama et al., Am. J. Obstet. Gynecol., 2000, 183, 1537-1543).”
Therefore, the art does not appear to offset the deficiencies of the specification. Merely describing a “sPLA2/sPLA2-IIA inhibitors” capable of treating a condition, disease or disorder (or COVID-19) when said sample (from the subject) has an elevated level of sPLA2/sPLA2-IIA. without sufficient detail relating to the genus of sPLA2/sPLA2-IIA inhibitor in the treating of a condition, disease or disorder (or COVID-19) when said sample (from the subject) has an elevated level of sPLA2/sPLA2-IIA does not allow the skilled artesian to reasonably conclude that the Applicants were in possession of the claimed invention in claim(s) 1-18, 20, and 25.
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.
Claim(s) 1-18, 20, and 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for A method of treating COVID-19 in a subject, comprising: a) assaying a sample from said subject for the level of secreted phospholipase A2-IIA (sPLA2-IIA); b) identifying said subject as having an elevated level of sPLA2-IIA relative to a population average of non-Covid 19 subjects; and c) administering LY315920 to said identified subject, does not reasonably provide enablement for treatment of any condition/disease/disorder, any level of sPLA2, or any sPLA2 inhibitor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
Claim 1 is drawn to a method of treating a condition, disease or disorder in a subject, comprising: a) assaying a sample from said subject for the level of a secreted phospholipase A2 (sPLA2); and b) administering an sPLA2 inhibitor to said subject when said sample has an elevated level of sPLA2.
Claim 5 is drawn to a method of treating a condition, disease or disorder in a subject, comprising: a) assaying a sample from said subject for the level of secreted phospholipase A2 isoform IIA (sPLA2-IIA); and b) administering an sPLA2-IIA inhibitor to said subject when said sample has an elevated level of sPLA2-IIA.
Claim 15 is drawn to a method of treating COVID-19 in a subject, comprising: a) assaying a sample from said subject for the level of an sPLA2; and b) administering an sPLA2 inhibitor to said subject when said sample has an elevated level of sPLA2.
The nature of the invention is complex in that an sPLA2 inhibitor must be capable of (1) treating any (1) condition, (2) disease, (3) disorder, or (4) COVID-19 in a subject comprising: a) assaying a sample from said subject for the level of a secreted phospholipase A2 (sPLA2); and b) administering an sPLA2 inhibitor to said subject when said sample has an elevated level of sPLA2. Also, in that an sPLA2-IIA inhibitor must be capable of (1) treating any (1) condition, (2) disease, or (3) disorder in a subject comprising: a) assaying a sample from said subject for the level of a secreted phospholipase A2 (sPLA2); and b) administering an sPLA2 inhibitor to said subject when said sample has an elevated level of sPLA2.
Breadth of the claims:
Regarding claim 1, the broadest reasonable interpretation is that the invention is drawn to a method of treating any/all conditions, any/all diseases, and any/all disorders in a subject comprising: a) assaying any type of sample from said subject for the level of any/all secreted phospholipase A2 (sPLA2); and b) administering any/all sPLA2 inhibitor to said subject when said sample has an elevated level of sPLA2. The claim broadly encompasses an embodiment where none of the conditions/diseases/disorders are treated in a subject when the sPLA2 is not elevated.
Regarding claim 5, the broadest reasonable interpretation is that the invention is drawn to a method of treating any/all conditions, any/all diseases, and any/all disorders in a subject comprising: a) assaying any type of sample from said subject for the level of secreted phospholipase A2-IIA (sPLA2-IIA); and b) administering any/all sPLA2-IIA inhibitor to said subject when said sample has an elevated level of sPLA2-IIA. The claim broadly encompasses an embodiment where none of the conditions/diseases/disorders are treated in a subject when the sPLA2-IIA is not elevated.
Regarding claim 15, the broadest reasonable interpretation is that the invention is drawn to a method of treating COVID-19 in a subject comprising: a) assaying any type of sample from said subject for the level of any/all secreted phospholipase A2 (sPLA2); and b) administering any/all sPLA2 inhibitor to said subject when said sample has an elevated level of sPLA2. The claim broadly encompasses an embodiment where a subject does have COVID-19 but is not treated when the sPLA2 is not elevated.
The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples:
Looking to the specification regarding (a) condition, disease or disorder, (b) any/all sPLA2, and (c) any/all sPLA2/sPLA2-IIA inhibitors.
Regarding condition, disease or disorder
“The present disclosure is not limited to particular conditions, diseases, or disorders. Examples include but are not limited to, a respiratory disorder, a trauma, a bacterial infection, septic shock, heart failure, disseminated intravascular coagulation or prolonged or new symptoms that develop after an infection such as acute COVID-19. In some embodiments, the respiratory disorder is or includes acute respiratory distress syndrome (ARDS). In some embodiments, the subject is infected with or has been infected with the SARS-CoV-2 virus. In some embodiments, the subject has one or more symptoms of COVID-19. In some embodiments, the subject is at increased risk of severe disease or death from the respiratory disorder (e.g., due to age over 65 or comorbidities). In some embodiments, the subject has PASC.”, (see page 3, 4th paragraph).
“Initially identified in circulation and synovial fluid of rheumatoid arthritis patients, sPLA2-IIA elevations occur in a variety of clinical conditions, including sepsis and systemic bacterial infections, adult respiratory disease syndrome (ARDS), atherosclerosis, cancer, and multiple organ trauma.”, (see page 10, paragraph 1, lines 7-10).
“Study design: This retrospective study analyzed 127 plasma samples from patients hospitalized at Stony Brook University Medical Center (Stony Brook, NY, United States) from January to July 2020. This study followed Good Clinical Practice guidelines and was approved by the central 5 10 15 20 25 30 institutional review board at Stony Brook University (IRB2020-00423). COVID-19 was diagnosed using the viral nucleic acid test (RT-PCR) per guidelines from Centers for Disease Control and Prevention (CDC). COVID-19 patients were classified into 3 groups: 1) mild = mild symptoms without pneumonia on imaging and discharged from inpatient care, 2) severe = respiratory tract or non-specific symptoms, pneumonia confirmed by chest imaging, oxygenation index below 94% on room air, and discharged from inpatient care, 3) deceased = expired during inpatient care.”, (Page 16, paragraph 1).
Regarding any/all sPLA2
“For example, in some embodiments, provided herein is a method of treating a condition, disease or disorder in a subject, comprising: a) assaying a sample from said subject for the level of any low MW, Ca dependent secreted phospholipase A2 (such as sPLA2-IIA or other secreted isoforms (e.g., PLA2G12B, PLA2G1B, PLA2G16, PLA2G5, PLA2G10, PLA2G2C, PLA2G2E, PLA2G7 or PLA2G2D)); and b) administering an sPLA2 (e.g., sPLA2-IIA) inhibitor to the subject when the sample has an elevated level of sPLA2.”, (see page 2, paragraph 6 to page 3 paragraph 1).
“The secreted phospholipase A2 (sPLA2) family includes 12 members (e.g., PLA2G12B, PLA2G1B, PLA2G16, PLA2G5, PLA2G10, PLA2G2C, PLA2G2E, PLA2G7 and PLA2G2D) and has several conserved characteristics, which include their low molecular weight (14-16 kDa), their requirement for high Ca2+ levels for catalytic activity, and the presence of a histidine and aspartic acid dyad in their catalytic site. Group IIA sPLA2 (sPLA2-IIA) known as "non pancreatic", "synovial", "platelet", "inflammatory", and "bactericidal" is the most studied sPLA2. Initially identified in circulation and synovial fluid of rheumatoid arthritis patients, sPLA2-IIA elevations occur in a variety of clinical conditions, including sepsis and systemic bacterial infections, adult respiratory disease syndrome (ARDS), atherosclerosis, cancer, and multiple organ trauma. During a human infection, sPLA2-IIA and other secreted PLA2 isoforms can be released from numerous activated cells including endothelial cells, platelets, haptic and smooth muscle cells, and a wide range of inflammatory cells.”, (see page 10, paragraph 1).
“Accordingly, provided herein are compositions and methods for blocking sPLA2 (e.g., sPLA2-IIA) (e.g., to treat COVID-19 and other disorders associated with elevated sPLA2-IIA. The present disclosure is not limited to a particular sPLA2. In some embodiments, the sPLA2 is a low MW, Ca dependent secreted phospholipase A2 (such as sPLA2-IIA or other secreted isoforms (e.g., PLA2G12B, PLA2G1B, PLA2G16, PLA2G5, PLA2G10, PLA2G2C, PLA2G2E, PLA2G7 orPLA2G2D)).”, (see page 11, paragraph 2).
“Proteomics was carried out utilizing the SomaScan Platform (4776 unique human protein targets). These data were analyzed from the 2021 study of Filbin et al. (Cell Reports Medicine 2, 100287 2021). In this study, patient blood samples were taken upon entering the hospital (day 0) and at day 3 and day 7 after hospital stay. FIG. 11 shows levels of the family of secreted PLA2s at each of the time points. Only 44 of4776 proteins follow the kinetics of continuing to increase in the deceased patient population. This included the secreted PLA2 isoforms, PLA2G2A, PLA2G10, PLA2G5, PLA2G2C, PLA2G1B, and PLA2G2E.”, (see working example 3, page 27).
Regarding any/all sPLA2/sPLA2-IIA inhibitors
“Any suitable sPLA2 (e.g., sPLA2-IIA) inhibitor may be utilized in the methods described herein. Examples include but are not limited to, antibodies, nucleic acids (e.g., antisense nucleic acids, siRNAs, shRNAs, miRNAs, etc.), and small molecules (e.g., varespladib methyl, AZD2716, 7,7-Dimethyleicosadienoic Acid (DEDA), oleyloxyethyl phosphorylcholine, luffariellolide, thioetheramide PC, 4-[(1-oxo-7-phenylheptyl)amino]-(4R)-octanoic acid, LY315920, oryS-[(1-oxo-7-phenylheptyl)amino]-4-(phenylmethoxy)-benzenepentanoic acid).”, (see page 3, paragraph 3).
To summarize the guidance of the specification and working examples: there are no working examples provided to show the treatment of any/all conditions/diseases/disorders comprising assaying samples for the level of sPLA2, and administering an sPLA2 inhibitor when the level of sPLA2 is elevated. The specification provides prophetic descriptions based on examples that are from retrospective samples of COVID-19 patients analyzed for their level of sPLA2. However, no there are no examples of administering any sPLA2 inhibitor and demonstrating the effects of treatment if a subject had elevated sPLA2.
Predictability and state of the art:
Looking to the prior art for treating any/all conditions/diseases or disorders when sPLA2 is elevated, Bradley et al (A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial of LY333013, a selective inhibitor of Group II Secretory Phospholipase A2, in the treatment of Rheumatoid Arthritis, The journal of Rheumatology, Volume 32, Issue 2, Pages 417-423, published March 1st, 2005) discloses:
“The activity of both sPLA2 and cytosolic phospholipase (cPLA2), a related enzyme, is increased by inflammatory stimuli such as bacterial lipopolysaccharide, tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß). The secretory and cytosolic PLA2 enzymes differ in their molecular weights, calcium dependency, and optimum pH2… Correlations have been found in patients with RA between the serum sPLA2 concentration and clinical markers of disease activity, e.g., swollen joints, elevated platelet count, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and depressed hemoglobin concentration. Expression of sPLA2 in RA synovial tissue correlates with histologic features of inflammation, e.g., lining layer thickness, and increased sPLA2 activity has been observed in RASF1. The chondrocyte is believed to be another source of SF sPLA2. Increased sPLA2 activity also has been observed in gut mucosa in inflammatory bowel disease and in serum in septic shock.”, (see page 417, column 1, paragraph 1; and page 417, column 2, paragraph 3 to page 418, column 1, paragraph 1).
Moreover, “Our study did not find a significant sustained benefit from administration of a potent inhibitor of sPLA2, which achieved high plasma concentrations. A dose-dependent response observed at week 1 was subsequently overtaken by the clinical improvement of the placebo control group. The transient response may be attributed to inhibition of the pre formed sPLA2 stored in and released from granules in platelets, mast cells, synoviocytes, and hepatocytes, perhaps followed by induction of accelerated synthesis of sPLA2... Nevertheless, the results of this study cast substantial doubt on the clinical importance of group II sPLA2 in partially-treated RA.”, (see page 422, column 1, paragraph 2 to column 2, paragraph 2).
PNG
media_image7.png
484
776
media_image7.png
Greyscale
Looking to the prior art for any/all sPLA2, Dennis et al (Phospholipase A2 Enzymes: Physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention, Chem Rev, Volume 111, pages 6130-6185, published September 12th, 2011) sPLA2 structure:
Dennis et al discloses in Table 2 all of the sPLA2 proteins, their molecular mass, and disulfide bonds. In Table 3 (shown below), Dennis et al discloses the domains of each sPLA2 protein.
Further, Dennis et al teaches the differences in the sPLA2 proteins.
“sPLA2s exhibit a large variety of cellular functions, although the specific function varies by group or subgroup. The major functions will be summarized below and include the ability to kill Gram-positive and Gram-negative bacteria, thereby affecting host defense against bacterial infections. sPLA2s also show antiviral activity. sPLA2s are expressed and released by human inflammatory cells including macrophages, monocytes, T cells, mast cells, and neutrophils, and increased concentrations of different isoforms of sPLA2s have been detected in the blood of patients with inflammatory and autoimmune diseases. sPLA2s also play a role in the hydrolysis of oxidized lipids in low- and high-density lipoproteins contributing to the development of atherosclerosis.”, (see page 6135, column 1, under section 2.3).
“There is a considerable body of evidence supporting the antibacterial functionality of sPLA2. GIIA sPLA2 has displayed antibacterial activity toward Grampositive bacteria including Staphylococcus aureus, Listeria monocytogenes, and others. The enzyme has also demonstrated antibacterial activity against some Gram-negative bacteria, such as E. coli and Salmonella typhimurium. High concentrations of GIIA sPLA2 are found in tears, where the majority of bactericidal action is due to GIIA sPLA2. The concentration of GIIA sPLA2 increases up to 500-fold in the serum samples of patients with severe acute diseases compared with healthy controls. High concentrations of GIIA sPLA2 have also been found in seminal plasma, inflammatory exudates, bronchoalveolar lavage, and intestinal lumen… In addition to GIIA, other sPLA2s also have antibacterial activity. The ranking of most to least potent sPLA2s against Gram-positive bacteria is GIIA >GX > GV > GXII > GIIE > GIB, GIIF for human, and GIIA > GIID > GV >GIIE > GIIC, GX > GIB, GIIF for murine. The antibacterial efficiency of a particular sPLA2 depends significantly on the highly positively charged protein surface. For example, the GIIA sPLA2 shows more antibacterial function than other sPLA2s; this may be related to its highly cationic nature (pI > 10.5).”, (Page 6136, column 1, paragraphs 2 to 4).
“The sPLA2s appear to play a role in several inflammatory diseases. The first evidence was from GIIA sPLA2, which is present at high concentrations in the synovial fluid of patients with rheumatoid arthritis. GIIA sPLA2-deficient mice have shown reduced signs of arthritis when compared with wild-type mice. Recently, GV sPLA2 has also been found in rheumatoid arthritis synovial fluid, but the expression was notably lower than that for GIIA sPLA2. However, GV sPLA2 may play an anti-inflammatory role rather than the normal pro-inflammatory role.”, (see page 6136, column 2, section 2.3.2).
Moreover, Dennis et al, Kawauchi et al, and Bennett et al teach the various sPLA2 inhibitors, for their use is decreasing sPLA2, which can be found in the Written Description Rejection.
The state-of-the-art teaches in Bradley et al that sPLA2 inhibitors do not necessarily work in the treatment of any/all conditions, diseases or disorders through clinical trials in treating rheumatoid arthritis with an sPLA2 inhibitor. Dennis et al teaches 17 different sPLA2 proteins with varying sizes, disulfide bonds, and functions. As well as Dennis et al, Kawauchi et al, and Bennett et al teach sPLA2 inhibitors. The art is silent on whether sPLA2 inhibitors can treat COVID-19 when sPLA2 levels are elevated. Thus, one of ordinary skill in the art would appreciate the unpredictability of treating any/all conditions, any/all disease, any/all disorders, and/or COVID-19 in a subject comprising: a) assaying any type of sample from said subject for the level of any/all secreted phospholipase A2 (sPLA2) or sPLA2-IIA; and b) administering any/all sPLA2 inhibitor to said subject when said sample has an elevated level of sPLA2 (or sPLA2-IIA).
Amount of experimentation necessary:
The quantity of experimentation required to carry out the scope of the invention is large. One would be required to (1) randomly select conditions, diseases, disorders, and COVID-19 that have an associated model and control system (e.g., tissue culture), (2) assay the condition/disease/disorder model for any/all sPLA2 (e.g., protein, mRNA, phospholipase levels correlated with sPLA2 activities), and (3) administer randomly selected sPLA2 inhibitors (e.g., antibodies, nucleic acids, small molecules) when sPLA2 in the samples is deemed “elevated”, all steps must cover the various functions of each broad genus for the capability of treating a condition, disease, disorder, or COVID-19, comprising: a) assaying a sample from said subject for the level of a secreted phospholipase A2 (sPLA2) or sPLA2-IIA; and b) administering an sPLA2 or sPLA2-IIA inhibitor to said subject when said sample has an elevated level of sPLA2 or sPLA2-IIA. This type of experimentation is not routine in the art and would require a large amount of inventive effort. Further considering any positive results (e.g., successful treatment of any/all conditions/disease/disorders or COVID-19) would amount to a significant advancement in the state-of-the-art, additional experimentation is considered undue.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention.
Therefore, claims 1-18, 20, and 25 are not considered to be fully enabled by the instant disclosure, however, they are scoped to a method of treating COVID-19 in a subject, comprising: a) assaying a sample from said subject for the level of secreted phospholipase A2-IIA (sPLA2-IIA); b) identifying said subject as having an elevated level of sPLA2-IIA relative to a population average of non-Covid 19 subjects; and c) administering LY315920 to said identified subject when said sample has an elevated level of sPLA2-IIA.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3, 5-8, 12-14, 17-18, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Abraham et al (Efficacy and Safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure, Crit Care Med, Volume 31, Issue 3, Pages 718-728, published March of 2003).
Regarding claim(s) 1-3, 5, 7, 17-18, and 20, Abraham et al discloses assaying samples from patients with sepsis and organ failure, and controls (page 719, column 3, paragraph 1), for levels of low kDa sPLA, sPLA2-IIA (see page 720, column 2, paragraph 2, and column 3, paragraphs 1 and 4), and administering small molecule sPLA2-IIA inhibitor, LY315920 to said patients (see page 720, column 1, paragraphs 2, 3, and 4).
Regarding claim 6, Abraham et al discloses multiple organ failure in table 3 titled Patient baseline characteristics, e.g., (1) organ failure criteria met, (2) respiratory organ failure, (3) cardiovascular organ failure, (4) hematology organ failure, and (5) renal organ failure (see page 722).
Regarding claim 8, Abraham et al discloses patients with ARDS in table 3 (see page 722).
Regarding claim 12, Abraham et al discloses a survival rate chart in Figure 2.
Regarding claim 13, Abraham et al discloses ages of patients in the treatment and placebo groups. The ages encompass patients over the age of 65 (see table 3).
Regarding claim 14, Abraham et al discloses assaying a patient’s respiratory rate in table 1 titled Systemic inflammatory response syndrome criteria.
Therefore, claim(s) 1-3, 5-8, 12-14, 17-18, and 20 are rejected as being anticipated by Abraham et al.
Claim(s) 1, 3, 5, 7-8, 12-14, 16-17, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nakos et al (Phospholipases A2 and platelet-activating-factor acetylhyrdrolase in patients with acute respiratory distress syndrome, Crit Care Med, Volume 33, Issue 4, Pages 772-779, published April of 2005).
Regarding claim(s) 1, 7-8, 17, and 20 Nakos et al discloses assaying samples from patients with acute respiratory distress syndrome (ARDS) or control patients (See table 1), for a level of sPLA2 (Figure 1), and administering sPLA2 small molecule inhibitor(s) (See table 4).
Regarding claim 3 and 5, Nakos et al discloses type IIA sPLA2 (See figure 4), and a sPLA2-IIA inhibitor, LY311727 (See table 4).
Regarding claim 12, Nakos et al discloses assaying sPLA2 activity from bronchoalveolar lavage from ARDS patients divided into two groups: alive and dead (See figure 3). Also see Figure 2 for the relationship between predicted mortality rate and PLA2 levels. Also see APACHE II score (See table 1).
Regarding claim 13, Nakos et al discloses subjects over 65 years of age in table 1 (see page 773).
Regarding claim 14, Nakos et al discloses setting ventilator settings to 10-18 breaths/min, and setting arterial oxygen saturation at a minimal level of 90% (See page 773, column 1, paragraph 3), as well as measured APACHE II scores (See table 1).
Regarding claim 16, Nakos et al discloses performing a western blot for sPLA2-IIA (see Fig. 4).
Claim(s) 1, 3, 5, 7-8, 12-14, 16-17, and 20 are rejected as being anticipated by Nakos et al.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable Nakos et al (Phospholipases A2 and platelet-activating-factor acetylhyrdrolase in patients with acute respiratory distress syndrome, Crit Care Med, Volume 33, Issue 4, Pages 772-779, published April of 2005) as applied to claim 1 above, and further in view of Kitsiouli et al (Phospholipase A2 subclasses in acute respiratory distress syndrome, Biochimica et Biophysica Act, Volume 1792, Pages 941-953, Published July 3rd, 2009).
Nakos et al does not teach (1) wherein said sPLA2 is a low MW, Ca++ dependent sPLA2 or (2) wherein said sPLA2 is selected from a group consisting of PLA2G12B, PLA2G1B, PLA2G16, PLA2G5, PLA2G10, PLA2G2C, PLA2G2E, PLA2G7 and PLA2G2D.
Kitsiouli et al teaches, “sPLA2s are low molecular weight secretory proteins (14–57 kDa) which usually contain 5–8 disulfide bonds (protein data bank number 1DB4) [30]. They possess a histidine in their active site, require mM levels of Ca2+ and show preference for anionic phospholipids as substrates, such as phosphatidylglycerol, a major component of surfactant phospholipids. Ten human genes encode the active secreted PLA2 enzymes [31]. Total lung extracts express sPLA2-IB, -IIA, -V, and -X. The prominent implication of sPLA2-IB and sPLA2-IIA in inflammation and ALI/ARDS has been established long ago in experimental models [32–34].”, (see page 942, column 2, paragraphs 1 and 2).
Kitsiouli et al further teaches, “sPLA2-IB, (pancreatic phospholipase A2, gene PLA2G1B), has a widespread tissue distribution, including lung… sPLA2-IB has been detected in serum of patients with acute lung injury but not in healthy controls. It can be used as a diagnostic and prognostic marker since the presence of the sPLA2-IB propeptide showed a 100% sensitivity for patients with ALI and 93% specificity for future development of ALI.”, (see page 942, column 2, paragraphs 3 and 4).
Thus, it would have been obvious to try to a person of ordinary skill before the effective filing date to assay the ARDS patients in Nakos et al for low molecular weight, calcium dependent sPLA2’s, such as sPLA2-IB (also known as PLA2G1B) as taught by Kitsiouli et al, to arrive at the claimed invention. One of ordinary skill in the art could have pursued assaying PLA2G1B with reasonable expectation of success and a predictable outcome because Kitsiouli et al teaches that sPLA2-IB has been detected in serum of patients with acute lung injury (ALI) and not in healthy controls, and further, sPLA2-IB can be used as a diagnostic and prognostic marker because the presence of the sPLA2-IB propeptide showed a 100% sensitivity for patients with ALI and 93% specificity for future development of ALI.
Therefore, claim(s) 2 and 4 are rejected as being unpatentable over Nakos et al in view of Kitsiouli et al.
Claim(s) 9, 15, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Nakos et al (Phospholipases A2 and platelet-activating-factor acetylhyrdrolase in patients with acute respiratory distress syndrome, Crit Care Med, Volume 33, Issue 4, Pages 772-779, published April of 2005) as applied to claim 1 above, and further in view of Wu et al (Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China, JAMA Internal Medicine, Volume 180, Issue 7, Pages 934-943, Published March 13th, 2020).
Nakos et al does not teach (1) wherein said subject is infected with or has been infected with the SARS-CoV-2 virus, (2) A method of treating COVID-19 in a subject (comprising the steps of claim 1), and (3) wherein said patient has a blood urea nitrogen (BUN) level greater than or equal to 16 mg/dl.
Regarding claim 9 and independent claim 15, Wu et al teaches all patients in the study have been infected with SARs-CoV-2 virus. More specifically, “In this study, we report the clinical characteristics and factors associated with developing ARDS after hospital admission and progression from ARDS to death in patients with COVID-19 pneumonia from a single hospital in Wuhan, China.”, (page 935, column 1, paragraph 2).
Regarding claim 25, Wu et al teaches, “As summarized in Table 4, older age (≥65yearsold), high fever (≥39 °C), comorbidities (e.g., hypertension, diabetes), neutrophilia, lymphocytopenia (as well as lower CD3 and CD4T-cellcounts), elevated end-organ related indices (e.g., AST, urea, LDH), elevated inflammation-related indices (high sensitivity C-reactive protein and serum ferritin), and elevated coagulation function–related indicators (PT and D-dimer) were significantly associated with higher risks of the development of ARDS.”, (see page 938, column 1, paragraph 4). Moreover, “For patients with ARDS who died, the value of liver damage indices (total bilirubin [difference, 2.60 μM; 95% CI, 0.30-5.20 μM; P = .03]), renal dysfunction indices (urea [difference, 1.50 mM; 95% CI ,0.50-2.70 mM; P = .004]), inflammation-related indices (IL-6 [difference, 3.88pg/mL; 95%CI, 2.20-6.13 pg/mL; P < .001]), and coagulation function indices (D-dimer [difference, 2.10 μg/mL; 95% CI, 0.89-5.27 μg/mL; P= .001]) were significantly elevated compared with patients with ARDS who survived.”, (see page 938, column 2, paragraph 2).
Table 3 of Wu et al indicates that all patients without ARDS had an average urea concentration of 4.30mM, compared to with ARDS which was an average of 5.80mM.
It is of note that plasma urea levels (those measured in Wu et al) can be converted to BUN levels, as BUN levels report one nitrogen and plasma urea levels indicates the entire molecule. Plasma urea molar mass is 2.14 times higher than BUN. BUN multiplied by 2.14 equals urea. Thus, 16 mg/dl of BUN is 34.24 mg/dl of plasma urea, however, when calculating molarity, this molar mass difference is taken into consideration.
PNG
media_image8.png
720
403
media_image8.png
Greyscale
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Nakos et al, i.e., assaying ARDS patients for sPLA2 and administering sPLA2 inhibitor, with Wu et al, i.e., assaying patients infected with SARS-Cov-2 and ARDS, to yield the predictable results of assaying subjects infected with the SARS-CoV-2 virus and treating said subjects with COVID-19 with the method of assaying for sPLA2, and administering an sPLA2 inhibitor when levels in subjects are elevated. One would have been motivated to assay such subjects infected with SARS-Cov-2 for sPLA2 because they are at a higher risk of progressing from COVID-19 to ARDS to death, as taught by Wu et al. It also would have been obvious to try to one of ordinary skill in the art before the effective filing date of the claimed invention to assay the ARDS patients in Nakos et al for urea levels, as taught by Wu et al. One of ordinary skill in the art could have pursued assaying BUN levels with reasonable expectation of success and a predictable outcome because Wu et al teaches that patients presenting with Covid-19 and ARDS have higher levels of plasma urea than those with just Covid-19, and converting when mg/dl to mM of BUN, the claimed invention indicates 5.7143 mM or greater, and the plasma urea levels taught by Wu et al are at 5.80mM, further indicating that urea levels and ARDS are positivity correlated.
Thus, claim(s) 9, 15, and 25 are rejected as being unpatentable over Nakos et al in further view of Wu et al.
Claim(s) 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Abraham et al (Efficacy and Safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure, Crit Care Med, Volume 31, Issue 3, Pages 718-728, published March of 2003) as applied to claim 5 above, and further in view of Wu et al (Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China, JAMA Internal Medicine, Volume 180, Issue 7, Pages 934-943, Published March 13th, 2020).
Abraham et al further teaches, “For patients who received study drug within 18 hrs from the onset of first sepsis-induced organ failure (Fig.3), there was a statistically significant dose-response effect associated with LY315920Na/S-5920 (p= .018). There was no significant difference in mortality in the low-dose LY315920Na/S-5920 group relative to placebo (31.4% vs.43.5%, respectively, p= .234), but there was a difference between high-dose LY315920Na/ S-5920 and placebo (20.8% vs. 43.5%, respectively, p =008).”, (see page 722, column 3, paragraph 1).
Abraham et al does not teach (1) wherein said subject has one or more symptoms of COVID-19 or (2) wherein said subject has PASC.
Regarding claim 10, Wu et al teaches initial symptoms among patients admitted to the hospital with confirmed COVID-19 with and without ARDS, such as fever, cough, dyspnea, and fatigue (See table 1 and table 3).
Regarding claim 11, Wu et al teaches “As reported by Huang et al, patients with COVID-19 present primarily with fever, myalgia or fatigue, and dry cough. Although most patients are thought to have a favorable prognosis, older patients and those with chronic underlying conditions may have worse outcomes. Patients with severe illness may develop dyspnea and hypoxemia within 1 week after onset of the disease, which may quickly progress to acute respiratory distress syndrome (ARDS) or end organ failure. Certain epidemiological features and clinical characteristics of COVID-19 have been previously reported.”, (see page 935, column 1, paragraph 2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effect filing date of the claimed invention to try to assay subjects for levels of sPLA2-IIA, as taught by Abraham et al, that present to the hospital with COVID-19 symptoms or PASC, as taught by Wu et al. One of ordinary skill in the art could have pursued assaying samples from patients with COVID-19 symptoms or PASC with reasonable expectation of success of elevated sPLA2-IIA and a predictable outcome because Wu et al teaches that patients presenting with severe COVID-19 illness, as measured by symptoms, may quickly progress to acute respiratory distress syndrome (ARDS) or end organ failure, and Abraham et al teaches that the that treatment with LY315920Na/ S-5920 was associated with an improvement in survival in patients treated within 18 hrs of the first sepsis-induced organ failure.
Therefore, claim(s) 10 and 11 are rejected as being unpatentable over Abraham et al in view of Wu et al.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim(s) 1-10 and 12-18 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1, 7-8, and 16-25 of copending Application No. 19/129,204 (reference application – hereinafter ‘204). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
Instant application
Copending application ‘204
1. A method of treating a condition, disease or disorder in a subject, comprising: a) assaying a sample from said subject for the level of a secreted phospholipase A2 (sPLA2); and b) administering an sPLA2 inhibitor to said subject when said sample has an elevated level of sPLA2.
1. A method of treating a condition, disease or disorder in a subject, comprising: a) assaying a first sample from said subject for the level of a secreted phospholipase A2 (sPLA2) at a first time point; b) assaying a second sample from said subject for the level of a secreted phospholipase A2 (sPLA2) at a second time point; c) repeating step b) at least one time at one or more third time points; and d) administering an sPLA2 inhibitor and/or a corticosteroid to said subject when the level of sPLA2 increases or decreases from said first time point to said third time point.
5. A method of treating a condition, disease or disorder in a subject, comprising: a) assaying a sample from said subject for the level of secreted phospholipase A2 isoform IIA (sPLA2-IIA); and b) administering an sPLA2-IIA inhibitor to said subject when said sample has an elevated level of sPLA2-IIA.
15. A method of treating COVID-19 in a subject, comprising: a) assaying a sample from said subject for the level of an sPLA2; and b) administering an sPLA2inhibitor to said subject when said sample has an elevated level of sPLA2.
3. The method of claim 1, wherein said sPLA2 is sPLA2- IIA.
8. The method of any of the preceding claims, wherein said sPLA2 is sPLA2-IIA.
4. The method of claim 1, wherein said sPLA2 is selected from the group consisting of PLA2G12B, PLA2G1B, PLA2G16, PLA2G5, PLA2G10, PLA2G2C, PLA2G2E, PLA2G7 and PLA2G2D.
7. The method of any of the preceding claims, said sPLA2 is selected from the group consisting of sPLA2-IB, sPLA2-IIA, sPLA2-IIC, sPLA2-II-D, sPLA2-II-E, sPLA2-II-F, sPLA2- III, sPLA2-V, sPLA2-X, sPLA2-XIIA, and sPLA2-XIIB.
6. The method of claim 1, wherein said condition, disease, or disorder is or includes multiple organ failure.
15. The method of any of the preceding claims, wherein said condition, disease, or disorder is or includes multiple organ failure.
7. The method of claim 1, wherein said condition, disease or disorder is selected from the group consisting of a respiratory disorder, a trauma, a bacterial infection, septic shock, heart failure, and disseminated intravascular coagulation.
16. The method of any of the preceding claims, wherein said condition, disease or disorder is selected from the group consisting of a respiratory disorder, a trauma, a bacterial infection, septic shock, heart failure, a bite from a venomous snake, and disseminated intravascular coagulation.
8. The method of claim 7, wherein said respiratory disorder is acute respiratory distress syndrome (ARDS).
17. The method of claim 16, wherein said respiratory disorder is acute respiratory distress syndrome (ARDS).
9. The method of claim 1, wherein said subject is infected with or has been infected with the SARS-CoV-2 virus.
18. The method of any of the preceding claims, wherein said subject is infected with or has been infected with the SARS-CoV-2 virus.
10. The method of claim 5, wherein said subject has one or more symptoms of COVID-19.
19. The method of claim 18, wherein said subject has one or more symptoms of COVID-19.
12. The method of claim 1, wherein said subject is at increased risk of severe disease or death from said condition, disease or disorder.
20. The method of any of the preceding claims, wherein said subject is at increased risk of severe disease or death from said condition, disease or disorder.
13. The method of claim 1, wherein said subject is over the age of 65.
21. The method of any of the preceding claims, wherein said subject is over the age of 65.
14. The method of claim 1, further comprising assaying one or more of the subject's respiration rate, oxygen saturation or pulmonary lesion progression.
22. The method of any of the preceding claims, further comprising assaying one or more of the subject's respiration rate, oxygen saturation or pulmonary lesion progression.
16. The method of claim 1, wherein said assaying comprises an immunoassay.
23. The method of any of the preceding claims, wherein said assaying comprises an immunoassay.
17. The method of claim 1, wherein said sPLA2 inhibitor is selected from the group consisting of a nucleic acid, an antibody, and a small molecule.
24. The method of any of the preceding claims, wherein said sPLA2 inhibitor is selected from the group consisting of a nucleic acid, an antibody, and a small molecule.
18. The method of claim 17, wherein said small molecule is selected from the group consisting of varespladib methyl, AZD2716, 7,7-Dimethyleicosadienoic Acid (DEDA), oleyloxyethyl phosphorylcholine, luffariellolide, thioetheramide PC, 4-[(1-oxo-7- phenylheptyl)amino]-(4R)-octanoic acid, LY315920, and yS-[(1-oxo-7-phenylheptyl)amino]- 4-(phenylmethoxy)-benzenepentanoic acid.
25. The method of claim 24, wherein said small molecule is selected from the group consisting of varespladib methyl, AZD2716, 7,7-Dimethyleicosadienoic Acid (DEDA), oleyloxyethyl phosphorylcholine, luffariellolide, thioetheramide PC, 4-[(1-oxo-7- phenylheptyl)amino]-(4R)-octanoic acid, LY315920, and yS-[(1-oxo-7-phenylheptyl)amino]-4- (phenylmethoxy)-benzenepentanoic acid.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Lewin et al (US 12,564,575 B2, published March 3rd, 2026, priority date of October 15th, 2019) discloses, “The present invention relates to the early treatment, including pre-diagnosis treatment, of sepsis and acute inflammatory syndromes such as systemic inflammatory response syndrome (SIRS) by PLA2 and metalloprotease inhibitors to improve the performance of antibiotics and outcomes prior to and after confirmation of the diagnosis of sepsis and/or SIRS in a patient or subject. Additional embodiments include methods of treating sepsis, anthrax and severe acute respiratory syndrome coronavirus (SARS and SARS-CoV2) and related inflammatory syndromes and compositions, including pharmaceutical compositions and blood sample compositions. In further embodiments, the present invention is directed to embodiments which evidence that LY315920, LY333013 and related sPLA2 inhibitors are particularly effective COVID-19/cytokine release syndrome therapeutics-prophylactics. In embodiments, the PLA2 inhibitor is varespladib (LY315920), methyl varespladib (LY333013), AZD2716-(R)-3-(5′-benzyl-2′-carbamoyl-[1,1′-biphenyl]-3-yl)-2-methylpropanoic acid—as a racemic mixture or separately, as the “R” enantiomer), compound 4 (3-(5′-benzyl-2′-carbamoyl-[1,1′-biphenyl]-3-yl)-propanoic acid) and LY433771 ((9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl) oxyacetic acid), a pharmaceutically acceptable salt thereof or a mixture thereof. In embodiments, the metalloprotease inhibitor is Prinomastat, Batimastat, marimastat or vorinostat dosed alone or in combination with preferred sPLA2 inhibitors for the treatment of infection, inflammatory and wound conditions arising from various causes. Methods and compositions for achieving accelerated treatment of wounds and burns, anthrax metalloprotease toxin (lethal factor) driven complications, ARDS, neo-natal and pediatric acute respiratory distress syndrome (neo-natal/pediatric ARDS), including meconium aspiration syndrome and other disease states and conditions are also disclosed.”, (see abstract).
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEXUS M TATGE whose telephone number is (571)272-0061. The examiner can normally be reached Monday-Friday: 8:30am to 5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637