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 .
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 Claim 23-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention as noted in the Office action of 01/16/2025, there being no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.
Claim Objections
Claim 13 is objected to because of the following informalities: the claim recites in step (ii) “wherein said priming, activating, and treating were performed as temporally distinct step”. The plurality agreement needs to be corrected so that the claim would recite “wherein said priming, activating, and treating were performed as temporally distinct steps”. Appropriate correction is required.
Withdrawn Rejections
The previous rejection of claims 13, 20-22 and 39 under 35 U.S.C. 112(b), regarding indefiniteness is withdrawn in light of Applicant’s amendments of claims.
The previous rejection of claims 13, 20-22 and 39 under 35 U.S.C. 101, regarding the claims being directed to a judicial exception, is withdrawn in light of Applicant’s amendments of claims.
The previous rejection of claim 39 under 35 U.S.C. 102(a)(1), as being anticipated by Frazier et al. (Pediatr Clin North Am. 2008 June ; 55(3): 647–xi), is withdrawn in light of Applicant’s amendments of the claim.
The previous rejections of claims 35-38 under 35 U.S.C. 103, regarding obviousness, are withdrawn in light of Applicant’s amendments of the claims.
New Rejections
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 13, 20-22 and 39 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Regarding claims 13 and 39, the amended claims recite “supraphysiological extracellular ATP conditions”. However, the term “supraphysiological” is not supported in the specification because the specification only provides support for two concentration for “supraphysiological” extracellular ATP (i.e., 0.9 and 3 mM). Thus, the claims do not have support for the broad genus of “supraphysiological” extracellular ATP conditions.
Also, none of the previous sets of claims recite “supraphysiological extracellular ATP conditions”, and the specification does not recite “supraphysiological extracellular ATP conditions”. The specification has support for only two concentrations (i.e., 0.9 and 3 mM) of the “supraphysiological extracellular ATP conditions” to induce P2X7 receptor activation (Specification, page 5, lines 18-21, “and ATP (3 mM, 30 min) treatment”; Drawings, Figure 5, e, “ATP (mM)”, “0.9” and “3”).
MPEP2163.02 recites “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. This conclusion will result in the rejection of the claims affected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph - description requirement, or denial of the benefit of the filing date of a previously filed application, as appropriate”. In the instant case, the term “supraphysiological extracellular ATP conditions” was introduced into the claims without proper support from the specification.
MPEP2163.06 further recites “Lack of written description is an issue that generally arises with respect to the subject matter of a claim. If an applicant amends or attempts to amend the abstract, specification or drawings of an application, an issue of new matter will arise if the content of the amendment is not described in the application as filed… If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981)… When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not "new matter" is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure”. In the instant case, the subject matter of “supraphysiological ATP conditions” was not properly described in the instant application as filed, and consequently it raises doubt as to possession of the claimed invention at the time of filing as discussed above in MPEP2163.02 and MPEP2163.06.
Claims 13, 20-22 and 39 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 for stratifying mortality risk in a sepsis patient by ex vivo priming and activation of the NLRP3 inflammasome in innate immune cells contained in a blood sample from a patient by inducing P2X7 receptor activation with two concentrations of supraphysiological extracellular ATP (i.e., 0.9 and 3 mM), does not reasonably provide enablement for the claimed method comprising the use of all other concentrations of “supraphysiological” extracellular ATP conditions. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case where there is a relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. In the instant case, the activation of P2X7 receptor with supraphysiological extracellular ATP is not well understood and is not fully documented in the prior art.
The current disclosure does not satisfy the enablement requirement for the step of inducing P2X7 receptor activation under all concentrations of “supraphysiological” extracellular ATP conditions that is not normally used and whether any necessary experimentation is "undue” as discussed In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The breadth of the claims:
Claims 13 and 39 are drawn to an in vitro method for stratifying mortality risk in a sepsis patient comprising within its scope a step of inducing P2X7 receptor activation under supraphysiological extracellular ATP conditions without specifying what concentrations to use for inducing P2X7 receptor activation. Both claims 13 and 39 do not specify the concentration to use for extracellular ATP and thus the claims are recited at a high level of generality.
The nature of the invention:
The invention teaches an in vitro method for stratifying mortality risk in a sepsis patient by ex vivo priming and activating the NLRP3 inflammasome in innate immune cells contained in a blood sample from a patient by inducing P2X7 receptor activation under supraphysiological extracellular ATP conditions. And determining the inflammasome responsiveness profile by detecting and comparing the levels of selected biomarkers of HMGB1, TNF-α and ASC-specks to reference levels or the level of one selected biomarker to a reference level. A reduction in the biomarker level or levels is indicative of immunoparalysis and increased mortality risk in sepsis.
The state of the prior art:
The prior art does not teach all concentrations of extracellular ATP for inducing P2X7 receptor activation and provides limited concentrations as noted by Virgilio et al. (Immunity 47, July 18, 2017, page 15, right column, second paragraph; page 22, left column, first paragraph). Virgilio teaches that ATP concentrations are as high as a few hundred micromolar at inflammatory or tumor sites and are in range for P2X7R activation (Page 22, left column, first paragraph). Virgilio does not teach what concentrations for extracellular ATP are used ex vivo to induce the activation of P2X7R. Shinohara et al. teaches using concentrations of 5mM of ATP ex vivo to study the activation of NLRP3 inflammasome (US 2012/0177632 A1, [0115]). Shinohara does not teach all concentrations of “supraphysiological” extracellular ATP for inducing P2X7 receptor activation. Moreover, Mello teaches that ATP cytotoxicity occurs in certain concentrations that would fall in the genus of supraphysiological extracellular ATP conditions (MBoC, Volume 25, October 1, 2014, abstract). Mello teaches that extracellular ATP promotes cell death in a dose- and time-dependent way (Page 2906, right column, third paragraph). Thus, the prior art does not teach all concentrations of “supraphysiological” extracellular ATP such that the claimed invention works as intended and does not teach which dos of extracellular ATP aretoxic to immune cells. , thus, evidencing unpredictability in practicing the full scope of the invention.
The level of one of ordinary skill:
The level of one of ordinary skill in the art is high and the artisan is a chemist or a scientist.
The level of predictability in the art:
Virgilio teaches using limited concentrations of extracellular ATP (Page 15, right column, second paragraph; page 22, left column, first paragraph), and Shinohara does not teach all concentrations of “supraphysiological” extracellular ATP to use for activating the inflammasome ex vivo. Also, while Mello teaches that extracellular ATP promotes cell death in a dose- and time-dependent way (Page 2906, right column, third paragraph), Mello falls short of teaching which dose of extracellular ATP is toxic to innate immune cells.
Because the prior art does not teach using all concentrations of “supraphysiological” extracellular ATP to induce P2X7 receptor activation, a skilled artisan would not have known which concentration of extracellular ATP to use and which one not to use from using the specification of the instant application. Furthermore, a skilled artisan would not have known which concentration of extracellular ATP would impose cytotoxicity to innate immune cells.
Thus, it is not known at what concentration will “supraphysiological” extracellular ATP impose toxicity to innate immune cells under investigation because the art does not show which concentrations of “supraphysiological” extracellular ATP to use to avoid cellular toxicity.
Therefore, there is a high level of unpredictability in the art because using “supraphysiological” extracellular ATP ex vivo to induce P2X7 receptor activation has not been documented as a common practice in prior art.
The amount of direction provided by the inventor:
The inventor provided directions on how to use two different concentrations of extracellular ATP (i.e., 0.9 and 3 mM) to induce P2X7 receptor activation (Specification, page 5, lines 18-21, “and ATP (3 mM, 30 min) treatment”; Drawings, Figure 5, e, “ATP (mM)”, “0.9” and “3”). However, the inventor did not teach all concentrations of “supraphysiological” extracellular ATP to use. Thus, the inventor provided limited number of concentrations of “supraphysiological” extracellular ATP to use for inducing P2X7 receptor activation.
The existence of working examples:
Although there are seven working examples that the inventor has provided in the specification, only two concentrations for “supraphysiological” extracellular ATP (i.e., 0.9 and 3 mM) are taught in the specification and drawings (Specification, page 5, lines 18-21, “and ATP (3 mM, 30 min) treatment”; Drawings, Figure 5, e, “ATP (mM)”, “0.9” and “3”). Thus, there isn’t enough examples to teach the genus of “supraphysiological” extracellular ATP conditions.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
As noted above, the inventor provided only two concentrations for “supraphysiological” extracellular ATP to induce P2X7 activation. Also, all the Examples of the instant case do not teach more than two concentrations for “supraphysiological” extracellular ATP to induce P2X7 receptor activation. Last, the prior art falls short of teaching all concentrations of extracellular ATP that are considered supraphysiological. Thus, there will be an undue amount of experimentation to be done by the skilled artisan based on the state of prior art and inventor’s guidelines of the instant case.
Therefore, the specification fails to disclose at least one method for using the claimed invention that bears a reasonable correlation to the entire scope of the claim, and thus the enablement requirement of 35 U.S.C. 112 is not satisfied. In the instant case, the specification teaches two concentrations of “supraphysiological” extracellular ATP to induce P2X7 receptor activation, whereas the claims have a much broader coverage of “supraphysiological” extracellular ATP.
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 35-39 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.
The term “sufficient to induce” in claims 13 and 39 is a relative term which renders the claims indefinite. The term “sufficient” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. A skilled artisan would not have been able to know from the claim language and the specification what is meant by sufficient to induce the activation and assembly of NLRP3 inflammasome in claims 13 and 39 respectively.
Regarding claim 35, the phrase “at least two inflammasome-associated biomarkers” in combination with the term "optionally" renders the claim indefinite because it is unclear whether the limitations following the term "optionally" are part of the claimed invention. See MPEP § 2173.05(d).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OMAR RAMADAN whose telephone number is (571)270-0754. The examiner can normally be reached Monday-Friday 8:30 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678