DETAILED ACTION
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 .
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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/28/2026 has been entered.
Priority
This application is a U.S. National Stage (371) application of PCT/EP2020/056729 filed on 03/12/2020 which claims priority to Foreign Application No. EP19382184.0 filed on 03/13/2019.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim Status
Claims 1-12 and 14-19 are cancelled at the Applicant’s request. Claims 13, 35 and 39 are currently amended, and the Applicant notes that no new matter is added. Claims 20-22 and 36-38 are previously presented. Claim 23-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention as noted in the Office action of 01/16/2025, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/27/2024.
Thus, claims 13, 20-22 and 35-39 are under examination.
Withdrawn Objections and Rejections
The previous objection to claim 13, regarding informalities, is withdrawn in light of Applicant’s amendments of the claim.
The previous rejection of claims 13, 20-22 and 39 under 35 U.S.C. 112(a), regarding written description requirement, is withdrawn in light of Applicant’s amendments of the claims.
The previous rejection of claims 13, 20-22 and 39 under 35 U.S.C. 112(a), regarding scope of enablement, is withdrawn in light of Applicant’s amendments of the claims.
New Rejections
Claim Rejections - 35 USC § 112(b)
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 13, 20-22 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.
Regarding claims 13 and 39, the claims recite “(ii) ex-vivo priming and activating the NLRP3 inflammasome in innate immune cells contained in said blood sample by inducing P2X7 receptor activation under extracellular ATP conditions, by treating the blood sample with one or more reagent
combinations selected from the group consisting of: LPS and ATP, LPS and nigericin, LPS and uric acid crystals, LPS and alum crystals, and intracellular LPS delivery”. It is not clear how the extracellular conditions of ATP are maintained because ATP is not part of all the groups of reagents from which a selection is to be made (i.e., LPS and nigericin, LPS and uric acid crystals, LPS and alum crystals, and intracellular LPS delivery). Also, it is not clear from the language of claims 13 and 39 if extracellular ATP conditions are present before adding the reagents because the claims recite “inducing P2X7 receptor activation under extracellular ATP conditions, by treating the blood sample with one or more reagent
combinations selected from the group consisting …”. The claims further recite that “wherein said priming, activating, and treating were performed as temporally distinct steps”, but it is not clear how the extracellular conditions of ATP are distinct from the reagents to add to the blood sample. Thus, a skilled artisan would not have been able to apprise the scope of the invention from the language used in claims 13 and 39, and therefore claims 13, 20-22 and 39 are deemed indefinite.
Claim 36-37 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of LPS and ATP, LPS and nigericin, LPS and uric acid crystals, LPS and alum
crystals, intracellular LPS delivery and other inflammasomes or NLRC4 and Pyrin inflammasomes is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the members are not considered to be functionally equivalent and do not have a common use that flows from a substantial structural feature for example. Specifically, claims 36-37 add species of “other inflammasomes” or “NLRC4 and Pyrin inflammasomes” respectively to a closed Markush list of “LPS and ATP, LPS and nigericin, LPS and uric acid crystals, LPS and alum crystals, intracellular LPS delivery”, and the added species in claims 36-37 are not considered to be functionally equivalent nor do they have a common use that flows from a substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 36-37 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 36-37 are expanding the closed Markush list of claim 35 (i.e., lipopolysaccharide (LPS) and adenosine triphosphate (ATP), LPS and nigericin, LPS and uric acid crystals, LPS and alum crystals, and reagents for intracellular delivery of LPS) by adding the species of “other inflammasomes” and “NLRC4 and Pyrin inflammasomes” respectively. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 (PHOSITA) 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 35-38 are rejected under 35 U.S.C. 103 as being unpatentable over Shinohara et al. (US 2012/0177632 A1) in view of Frazier et al. (Pediatr Clin North Am. 2008 June ; 55(3): 647–xi).
Regarding claim 35, the claim recites:
“A kit for determining NLRP3 inflammasome activation in blood sample obtained from a sepsis patient, the kit comprising:
a. a buffer suitable for diluting a blood sample obtained from the patient;
b. one or more reagents suitable for ex vivo priming and activation of NLRP3
inflammasome in innate immune cells contained in the blood sample, said reagents comprising one or more reagent combinations selected from the group consisting of: lipopolysaccharide (LPS) and adenosine triphosphate (ATP), LPS and nigericin, LPS and uric acid crystals, LPS and alum crystals, and reagents for intracellular delivery of LPS;
c. detection reagents for determining the concentration levels of at least two
inflammasome-associated biomarkers, wherein at least one of said biomarkers is ASC-specks, and wherein another of said biomarkers is selected from HMGB1 or TNF-α; and
d. instructions for use requiring ex vivo priming and activation of the blood sample prior
to biomarker detection, and for comparing the detected biomarker levels to
corresponding reference levels obtained from a healthy individual subjected to the same ex vivo treatment to assess inflammasome responsiveness”.
Applicant is reminded that a kit claim is examined in so far as the actual components of the kit and not in the intended use. The instructions are drawn to the intended use of the kit. Moreover, it is noted that detection of the biomarkers is any one of HMGB1 or TNF-α and in addition to ASC-specks.
Applicant is further reminded that claims 36-37 do not eliminate the prior art selection of ATP and LPS, but merely adds an improper Markush species as cited above in the112(d) and improper Markush rejections. Therefore, the teachings and suggestions of Shinohara and Frazier still applies to claims 36-37 and are included in this rejection.
Regarding claim 35, Shinohara teaches a kit for determining NLRP3 inflammasome activation (Page 9, [0083]; page 14, claims 14-16).
Shinohara teaches a buffer (Page 9, [0083]; page 14, claims 14-16) but does not state that it is suitable for diluting a blood sample obtained from a patient. However, it would have been understood that a buffer would dilute a blood sample upon adding the buffer to the sample.
Shinohara teaches reagents suitable for activation of NLRP3 inflammasome in blood cells (Page 9, [0083]; page 14, claims 14-16).
Shinohara teaches reagents for determining the concentration level of ASC-specks (Page 9, [0083]).
Shinohara teaches directions for comparing the concentration level of the at least one biomarker to the concentration level in a healthy patient (Page 1, [0008-0009]; page 6, [0055]; page 9, [0083]).
Regarding claim 36-37, Shinohara teaches that wherein the reagents are selected from the group consisting of LPS and ATP (Page 9, [0083 and [0087]; page 10, [0088]).
Regarding claim 38, Shinohara teaches that wherein the reagents for determining the concentration level of the at least one biomarker are those that can be used for an enzyme-linked immunosorbent assay (page 7, [0066]; page 9, [0083]; page 10, [0088]) and the reagents for determining the concentration level of ASC-specks are those that can be used for flow cytometry (Page 6, ([0060]; page 7, [0066]; page 9, [0083]).
Regarding claim 35, Shinohara does not teach using reagents for determining the concentration level of one biomarker selected from HMGB1 or TNF-α.
Regarding claim 35, Frazier teaches using a reagent for determining the concentration level of an induced TNFα as a biomarker of immunoparalysis (Page 5, first paragraph, “This threshold value may be different in another laboratory if other reagents and experimental methods are used. It bears re-emphasizing that this type of measurement does not reflect circulating TNFα levels in the plasma, but rather reflects the ability of a patient’s blood to make TNFα when it is needed”).
It would have been obvious for a PHOSITA at the time the application was filed to add Frazier’s detection reagents for determining the concentration levels of TNF-α to Shinohara’s kit to note the activation of NLRP3 inflammasome in blood cells because Frazier noted that critically ill patients are at high risk for the development of nosocomial infection and death when there is a sign of reduced inflammatory response demonstrated by prolonged, severe reductions in ex vivo TNF-α production (Page 1, Synopsis). Shinohara further mentioned that the review of the medical history of a patient with inflammatory disease could reveal the presence of a microbial infection [0020], and the absence of inflammasome activity [0067]. Shinohara further mentioned that a patient with an inflammatory disease could have sepsis (Page 7, [0067]). A PHOSITA would have had a reasonable expectation of success in combining the methods of Frazier and Shinohara because the methods are directed to detecting markers involved in an inflammatory response.
It would have been obvious for a PHOSITA to use the kit of Shinohara with the TNFα biomarker of Frazier to identify a patient with sepsis of being at risk of death.
Claim 36-37 is rejected under 35 U.S.C. 103 as being unpatentable over Shinohara et al. (US 2012/0177632 A1) and Frazier et al. (Pediatr Clin North Am. 2008 June ; 55(3): 647–xi) as applied to claim 35 above, and further in view of Canna et al. (Nature Genetics, Volume 46, Number 10, October 2014).
Claim 36 recites:
“The kit of claim 35, wherein the reagents are selected from the group consisting of LPS and ATP, LPS and nigericin, LPS and uric acid crystals, LPS and alum crystals, intracellular LPS delivery and other inflammasomes”.
And regarding claim 37, the claim recites:
“The kit of claim 36, wherein the other inflammasomes are selected from NLRC4 and Pyrin inflammasomes”.
The Applicant is reminded to note that kit’s claim 37 is drawn to claims 35 and 36 with the added limitation of “wherein the other inflammasomes are selected from NLRC4 and Pyrin inflammasomes”. The kit’s claim 37 now reads on the embodiment of where the reagents are actually selected from NLRC4 and Pyrin inflammasomes.
Regarding claims 36-37, the previous teachings of Shinohara and Frazier are previously discussed.
Regarding claim 36, Shinohara does not teach other inflammasomes.
Regarding claim 37, Shinohara does not teach that wherein the other inflammasomes comprises NLRC4 and Pyrin inflammasomes.
Regarding claim 37, Canna teaches that the other inflammasomes comprises NLRC4 (Abstract).
It would have been obvious for a PHOSITA at the time the application was filed to substitute the NLRP3 inflammasome of Shinohara’s method with NLRC4 inflammasome of Canna and biomarker of Frazier because it would have been helpful to note the response of different inflammasomes to treatment in an unresponsive patient with an inflammatory disease. Canna noted the involvement of NLRC4 in human disease and suggested it to be a new target for therapy (Abstract), and Frazier noted that the inability to mount an inflammatory response places the patient at risk for death from secondary infections and persistent organ failures (Page 1, Introduction). A PHOSITA would have had a reasonable expectation of success in combining the methods of Canna, Frazier and Shinohara because the methods are directed to detecting markers involved in inflammatory responses.
It would have been obvious for a PHOSITA to detect the activation of different inflammasomes in a patient with an inflammatory disease to predict the response of the patient to treatment.
Conclusion
No claims are allowed.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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