DETAILED ACTION
Response to Amendment
Applicant’s response to the office action filed on October 29, 2025 has been entered. The claims pending in this application are claims 16-30 wherein claims 24-30 have been withdrawn due to the restriction requirement mailed on June 24, 2025. The objections and rejection not reiterated from the previous office action are hereby withdrawn in view of applicant’s amendments filed on October 29, 2025. Claims 16-23 will be examined.
Specification
The substitute specification filed on October 29, 2025 has not been entered because it does not conform to 37 CFR 1.125(b) and (c) since, in view of original filed specification, International Patent Application No. PCT/EP2021/056529, filed on March 15, 2021 and European Patent Application No. EP 20163892. 1, filed on March 19, 2020 in the first paragraph of the substitute specification, the phrase “the entire disclosures of which are hereby incorporated by reference in their entirety” in the first paragraph of the substitute specification is a new matter.
Claim Objections
Claim 23 is objected to because of the following informalities: (1) there are two “ECFP” in the claim; (2) “GFPS65T”, “GFPuv”, “HcRed”, “t-HcRed”, “DsRed2”, “mRFP1”, “paGFP”, “mKalamal”, “SCFP3C”, “mTFP1”, “mUKG”, “SYFP2”, “ɭȠKok”, “mK02”, “TagRFP”, “TagRFP-2”, “TagRFO657”, “IFP1.4” and “iRFP” are abbreviations. They can be used after whole phrases representing these abbreviations appear once; and (3) “Czurite” should be removed from the claim since it is not a protein but is a soft, deep-blue copper carbonate mineral.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 23 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 23 is rejected as vague and indefinite since Emerald, Topaz, Sirius, Sapphire, Cerulean, Clover, Citrine, Venus, and Morange are trademarks because, according to MPEP 2173.05 (u), the presence of a trademark or trade name in a claim is not, per se, improper under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. Please clarify.
Response to Arguments
In page 12, second and third paragraphs of applicant’s remarks, applicant argues that “[R]egarding claim 23, all trademark terms have been removed and replaced with generic descriptions of the fluorescent proteins, such as ‘green fluorescent protein,’ ‘blue fluorescent protein,’ and ‘cyan fluorescent protein,’ which are well-understood terms in the art and are supported by the specification. As-Filed Specification, paragraphs [99]-[100]. Therefore, for at least these reasons, Applicants respectfully request that the rejection of claims 16-23 under 35 U.S.C. § 112 (b) be withdrawn”.
The above argument has been fully considered but it is not persuasive toward the withdrawal of the rejection since applicant has not removed the trademarks, Emerald, Topaz, Sirius, Sapphire, Cerulean, Clover, Citrine, Venus, and Morange, from claim 23.
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.
Claims 16-23 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Percherancier et al., (US 2018/0030108 A1, published on February 1, 2018).
Regarding claim 16, 17, and 21-23, since the phrase “a channel fusion subunit comprising an ion conducting channel subunit fused to a probe” can be read as a channel fusion subunit comprising an ion conducting channel subunit wherein the channel fusion subunit has an ability to be fused to a probe, the probe is not a structural limitation of claim 16 and the probe comprising an ion sensor that is sandwiched between at least one bioluminescent donor molecule and at least one fluorescent acceptor molecule is fused to the N-terminal, C-terminal, or within an intracellular or extracellular loop of said channel subunit via either the bioluminescent donor molecule or the fluorescent acceptor molecule and can be artificially made. Thus, Percherancier et al., teach that a channel fusion subunit (eg., YFP-hTRPV1-rLuc) comprising an ion conducting channel subunit fused to a probe (ie., having an ability to be fused to a probe), wherein the probe comprises an ion sensor that is sandwiched between at least one bioluminescent donor molecule and at least one fluorescent acceptor molecule, wherein the probe is fused to the N-terminal, C-terminal, or within an intracellular or extracellular loop of said channel subunit via either the bioluminescent donor molecule or the fluorescent acceptor molecule, and wherein said bioluminescent donor molecule and fluorescent acceptor molecule are selected so that the emission spectrum of the bioluminescent donor molecule overlaps with the absorbance spectrum of the acceptor molecule, making possible the non-radiative energy transfer between the bioluminescent energy donor and the fluorescent acceptor through nonradiative dipole-dipole coupling as recited in claim 16, the ion conducting channel subunit (eg., hTRPV1) is a voltage-dependent ion channel as recited in claim 17, the bioluminescent donor molecule is a Renilla luciferase (ie., rLuc) as recited in claim 21, the bioluminescent donor molecule is a non-luciferase bioluminescent protein chosen among β-galactosidase, lactamase, horseradish peroxidase, alkaline phosphatase, β-glucuronidase, and β-glucosidase as recited in claim 22, and the acceptor molecule is yellow fluorescent protein (YFP) as recited in claim 23 (see paragraphs [0006] and [0024] to [0037], [0108], [0109], and [0115] to [0118]).
Regarding claims 18-20, since, as mentioned above, the probe is not a structural limitation of claim 1 and the probe comprising an ion sensor that is sandwiched between at least one bioluminescent donor molecule and at least one fluorescent acceptor molecule, is fused to the N-terminal, C-terminal, or within an intracellular or extracellular loop of said channel subunit via either the bioluminescent donor molecule or the fluorescent acceptor molecule and can be artificially made, Percherancier et al., teach that the ion sensor is a sensor to calcium, potassium, sodium, chloride ions or a sensor to ionic strength as recited in claim 18, the ion sensor is chosen among calcium binding proteins, including troponin C calcium sensitive domain and calmodulin calcium binding protein, potassium binding proteins (KBP) as recited in claim 19, and a linker between the ion conducting channel subunit and the probe as recited in claim 20.
Therefore, Percherancier et al., teach all limitations recited in claims 16-23.
Response to Arguments
In page 12, fourth paragraph bridging to page 14, last paragraph of applicant’s remarks, applicant argues that “[N]ewly amended claim 16 recites a channel fusion subunit comprising an ion conducting channel subunit an ion sensor that is sandwiched between at least one bioluminescent donor molecule and at least one fluorescent acceptor molecule, wherein the probe is fused to the N-terminal, C-terminal, or within an intracellular or extracellular loop of said channel subunit via either the bioluminescent donor molecule or the fluorescent acceptor molecule, and wherein said bioluminescent donor molecule and fluorescent acceptor molecule are selected so that the emission spectrum of the bioluminescent donor molecule overlaps with the absorbance spectrum of the acceptor molecule, making possible the non-radiative energy transfer between the bioluminescent energy donor and the fluorescent acceptor through nonradiative dipole-dipole coupling. The Examiner has alleged that Percherancier anticipates claim 16 by teaching a YFP-hTRPV1-rLuc construct and has further alleged that ‘the phrase ‘a channel fusion subunit comprising ‘an ion conducting channel subunit bound to a probe’ can be read as a channel fusion subunit comprising an ion conducting channel subunit wherein the channel fusion subunit has an ability to be bound to a probe’ and that ‘the probe is not a structural limitation of claim 1.’ Office Action, page 6. Applicants respectfully disagree with the rejection and submits that Percherancier fails to anticipate claim 16 because it does not disclose each and every element as recited in the claim” and “[T]he Examiner’s interpretation that the probe is not a structural limitation of claim 16 is incorrect. Claim 16 explicitly recites ‘a channel fusion subunit comprising an ion conducting channel subunit fused to a probe, wherein the probe comprises an ion sensor that is sandwiched between at least one bioluminescent donor molecule and at least one fluorescent acceptor molecule." This language makes clear that the probe with its specific structural arrangement is a required structural element of the claimed fusion subunit’. Percherancier discloses a YFP-hTRPV1-RLuc construct where YFP and RLuc are fused to the N- and C-termini of TRPV1, respectively. As described in Percherancier, this construct measures ‘BRET signals from voltage-dependent ion channels, TRPV1, TRPV3 or TRPV4, which N- and C-termini have been fused to YFP and to luciferase, respectively’ and ‘activation of the channels following for example agonist exposure or cell culture temperature increase results in a change of the conformation of the monomer subunits which result in a modification of either or both the distance and the orientation of the donor and acceptor molecules in N- and C-terminal ends of the channels.’ Percherancier et al., paragraph [0167]. However, Percherancier's construct lacks the specific structural arrangement required by claim 16. The claimed channel fusion subunit requires an ion sensor that is sandwiched between the bioluminescent donor molecule and fluorescent acceptor molecule, which is fundamentally different from Percherancier's terminal fusion construct that merely places donor and acceptor molecules at the N- and C-termini of the channel without any intervening ion sensor structure. Percherancier’s construct measures general conformational changes in response to chemical activators like capsaicin, as demonstrated by BRET signal changes when ‘the BRET signal in HEK293T cells expressing the YFP-hTRPVl-rLuc fusion protein was measured after incubation of the cells in presence of different concentrations of capsaicin.’ Percherancier et al., paragraphs [0185]-[0186]. However, Percherancier’s approach lacks the specifically claimed configuration in which an ion sensor is sandwiched between the donor and acceptor molecules, and thus merely reports overall conformational changes in the channel protein, which may or may not correlate with actual pore opening and ion flux across the membrane. In other words, the observed conformational rearrangement does not necessarily reflect the functional state of the channel or confirm the occurrence of ion diffusion through the pore. Since Percherancier fails to disclose ‘a probe comprising an ion sensor that is sandwiched between at least one bioluminescent donor molecule and at least one fluorescent acceptor molecule’ as explicitly recited in claim 16, it cannot anticipate claim 16. Claims 17-23 depend from claim 16 and are allowable for at least the same reasons as claim 16”.
The above argument has been fully considered but it is not persuasive toward the withdrawal of the rejection. Although applicant argues that “[T]he Examiner’s interpretation that the probe is not a structural limitation of claim 16 is incorrect”, since claim 16 does not require that a channel fusion subunit comprising an ion conducting channel subunit and a probe, the phrase “a channel fusion subunit comprising an ion conducting channel subunit fused to a probe” can be read as a channel fusion subunit comprising an ion conducting channel subunit wherein the channel fusion subunit has an ability to be fused to a probe, the probe is not a structural limitation of claim 16, and the probe comprising an ion sensor that is sandwiched between at least one bioluminescent donor molecule and at least one fluorescent acceptor molecule is fused to the N-terminal, C-terminal, or within an intracellular or extracellular loop of said channel subunit via either the bioluminescent donor molecule or the fluorescent acceptor molecule and can be artificially made.
Conclusion
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.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph. D., whose telephone number is (571)272-0746. The examiner can normally be reached Monday to Friday, 9 AM to 5 PM.
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/FRANK W LU/
Primary Examiner, Art Unit 1683
February 2, 2026
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