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 .
Response to Amendment
Claims 2-3 and 12 are cancelled. Claims 1, 4, 6, 8, and 10 have been amended as requested in the amendment filed on 16 April 2026. Following the amendment, claims 1, 4-11, 13-20 are pending in the instant application.
Claims 14-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
Claims 1, 4-11, and 13 are under examination in the instant office action.
Specification
Please note that Table 1 at paragraph [0047] appears to state that SEQ ID NOs: 1 through 4 are amino acid sequences and SEQ ID NOs: 5 through 8 are DNA. This is the reverse, according to the sequence listing, SEQ ID NOs: 1 through 4 are DNA sequences and SEQ ID NOs: 5 through 8 are amino acid sequences.
Withdrawn Objection:
Paragraph [0027] of the specification has been amended to remove the browser-executable code. Therefore the objection is withdrawn.
Withdrawn Rejection:
Claim 12 has been cancelled, which obviates the rejection under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph set forth in the previous Office action.
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.
As currently amended, Claims 1, 4-10, and 13 stand as 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 for reasons of record in the previous Office action.
As currently amended, the claims have been amended to recite a “synthetic luciferase” and “a second domain that binds a ligand, wherein the ligand is a neurotransmitter”.
In Remarks filed 16 April 2026, Applicant argues that one of ordinary skill in the art can easily envision the claimed bioluminescent indicator with its domains (pg. 8, first full paragraph).
This is not persuasive because the claims still encompass genera while the specification fails to disclose either sufficient description of a representative number of species, or 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 function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
The claims recite a synthetic luciferase, and the specification discloses: “evolving firefly luciferase to use a synthetic substrate to create AkaLuc which produces near infrared bioluminescence. See, for example, Iwano, S. et al. Science 359, 935-939 (2018), which is incorporated herein by reference” (paragraph [0007]) and “BLING 0.2 comprises NanoLuc®, a synthetic luciferase split between amino acids 66 and 67, with an Igκ leader sequence for cell surface display. BLING 0.3 comprises NanoLuc® large and small portions, split between amino acids 159-160” (paragraph [0064]). AkaLuc and NanoLuc® are the only two synthetic luciferases disclosed within the specification, and yet the claims encompass any synthetic luciferase, including those that have yet to be discovered/invented. Thus, the specification fails to teach a representative number of species within the genus as a whole.
Lastly, as amended the claims encompass any ligand that binds any neurotransmitter. In contrast the specification provides only adequate written description for Glutamate (BioLuminescent Indicator of the Neurotransmitter Glutamate a.k.a. BLING see Table 1 at paragraph [0046]) and dopamine binding variants (DLume of paragraph [0075]). The genus of neurotransmitters is vast and glutamate and dopamine are not representative of the genus as a whole.
Lastly, depending claim 6 recites the leader domain comprising at least 95% sequence identity to an IgK leader sequence; depending claim 8 recites a transmembrane domain comprising at least 95% sequence identity to PDGFRbeta; and claim 10 recite at least 95% sequence homology to SEQ ID NOs: 5, 6, 7, and 8. There is absolutely no written description within the specification providing for which 5% of the amino acids within each of these domains may be altered/substituted/deleted such that the invention retains the functional requirement of a bioluminescent indicator. Therefore, the disclosure has failed to provide adequate written description of the identifying characteristics such as structure or other physical and/or chemical properties that must be retained and those that may be altered. Therefore, the disclosure as filed has failed to provide adequate written description or a representative number of species for those sequences that are 95% identical and yet retain function.
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, or representative number of species, the specification does not provide adequate written description of the claimed genus, and Claims 1, 4-11, and 13 stand as 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.
As currently amended, Claims 1, 4-10, and 13 stand as 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 bioluminescent indicator comprising a bioluminescent indicator comprising the sequences of SEQ ID NOs: 5 through 8 and 11 through 13, does not reasonably provide enablement for any other bioluminescent indicator encompassed by the broad scope of the claims.
On page 8 of Remarks, Applicant traverses this rejection on the following grounds. On Remarks page 8 second to last paragraph, Applicant states: “In support thereof, please see the enclosed book citation at section 2: Engineering Bioluminescent Neurotransmitter Sensors. "For example, the binding domain can be changed so that the sensor detects serotonin instead of ACh." Applicant also asserts that by increasing the sequence identity to 95% with only a 5% deviation using standard biotechnology techniques and software, the claims are now enabled.
This is not persuasive because a person having ordinary skill would have to make multiple variants having 95% identity and test their bioluminescence in order to enable the invention commensurate in scope with the breadth of the claims. Further, a person having ordinary skill would have to make a substantial inventive contribution in order to make bioluminescent sensors for neurotransmitters other than the Glutamate sensors consisting of BLING 0.1, 0.2, 0.3 and 1.0 (Table 1, paragraph [0046]) and the dopamine binding sensors consisting of DLume 1.0, 2.0 and 3.0 (Table 3 at paragraph [0076]).
In contrast to the breadth of the instant claims, what is enabled by the disclosure is narrow. The specification discloses a bioluminescent indicator consisting of the SEQ ID NOs: 5 through 8. There is no guidance or direction as to which 5% of the amino acids may be altered such that the invention retains the functional requirements of the claims. In other words, there is no guidance or direction within the disclosure as filed as to what 5% of the residues within each of these sequences can be substituted/deleted/modified while still maintaining the function of the bioluminescent indicator. Therefore, the specification does not provide enabling support for how to make the invention commensurate in scope with what is claimed.
The examiner maintains the position that a person having ordinary skill in the art would have to make multiple proteins comprising sequences in which 5% of the residues are substituted/deleted/modified and demonstrate that these constructs maintain the ability to luminesces upon ligand binding. Further, without guidance from the disclosure as filed, a skilled artisan would have to make bioluminescent molecules de novo, which bind to neurotransmitters other than glutamate and dopamine (i.e. GABA, Glycine, Serotonin, nitric oxide, acetylcholine, epinephrine, Histamine). The amount of experimentation required in order to make and use these without enabling guidance, goes well-beyond what is considered ‘routine’ within the art, and constitutes undue further experimentation in order enable the invention, commensurate in scope with the breadth of the claims, with a reasonable expectation of success. For all of these reasons, Claims 1, 4-11, and 13 stand as rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Allowable Subject Matter
Claim 11 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1, 4-10, and 13 are rejected.
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 STACEY NEE MACFARLANE whose telephone number is (571)270-3057. The examiner can normally be reached M-F 7:30-5 (EST) & Sat. A.M..
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/STACEY N MACFARLANE/ Examiner, Art Unit 1675
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