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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/24/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of Claims
Claims 1-4, 7-10, 15-18, 20-25, and 27-28 are pending and under examination.
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.
Claims 1-4, 7-10, 15-18, 20-25, and 27-28 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.
Regarding claim 1: The claim recites that a chemosensory opsin activation detection element, comprising one or more chemosensory opsins; wherein the detection element is configured to generate a measurable signal in response to activation by binding of a chemical ligand. The claim encompasses use of any opsin in the activation detection element. However, the specification only provided experimental support for OPN3 and OPN1SW as demonstrated in the Examples (e.g., TANGO assays and calcium flux assays using specific compounds).
It is submitted that “[s]ince the first sequence of an opsin, bovine rhodopsin, was determined by conventional protein sequencing in 1982 and cDNA sequencing in 1983, more than 1,000 opsins have been identified.” (See Terakita p. 213.1, col. 1, last para). It is known that “[t]he molecular phylogenetic tree shows three large clusters, and detailed analyses have revealed that the opsin family is divided into seven there is less than about 25% amino-acid similarity between subfamilies but more than about 40% among members of a single family.” (See Terakita p. 213.1, col. 1-2, last para). As such it was known that opsins represent a diverse group of proteins.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), 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 inventor was in possession of the claimed genus (See MPEP 2163 II 3 (ii)).
Given the requirement under written description, and the diversity of opsins, indicated above, in view of the limited disclosure of the specification, it is submitted that demonstration of a chemosensory activation detection element for two opsins – OPN3 and OPN1SW does not constitute demonstration is not sufficient for disclosure of possession of activation element for all known and unknown opsins.
As such it is submitted that the claim lacks written description. Similar rejection also applies to claim 15.
Claims 2-4, 7-10, 15-18, 20-25, and 27-28 inherit the rejection due to their dependency.
Claims 2-3 and 16-17 require variants, homologs, paralogs or orthologs of OPN3 and/or OPN1SW. The claims encompass a large group of proteins that have no disclosure in the specification. The specification only describes use of human OPN3 and OPN1SW (See Example 1). Nor does the specification teach that all paralogs, homologs and orthologs of these proteins behave and function in the same predictable, manner. Further, variants can include truncations, insertions, domain swaps among other changes. A person of ordinary skill in the art, based on the specification alone, will not understand that the Applicants had possession of the entire scope of the claim.
Claim 23-24 and 27 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
With regards to the breadth of the instant claims: Applicants claims are broadly drawn methods of method of measuring the activation of a chemosensory opsin by the binding of a chemical ligand, wherein the ligand “putatively” activates the opsin and masks a bitter taste. Similarly claims 23 and 24 are directed to any and all tastants or olfactants.
The specification showed that OPN3 and OPN1SW can be expressed in cell-based assays and activated by chemical compounds to generate measurable signals (Calcium flux, TANGO, etc. ) The specification showed that certain compounds, that also had characteristics of tastants produced activation of opsins, which was validated in vivo and in vitro.
There are no examples where any composition that masks or inhibits bitter flavor produces activation of the tested opsins. Similarly, there are no specific common structures of tastants or olfactants that do or do not cause the desired effect. Therefore, there is a gap between the teachings and examples provided in the disclosure and the subject matter claimed.
In looking to the art for guidance, it is noted that there are no catalogs of bitter taste inhibitors. For example, Ley taught that homoeriodictyol can mask bitter taste (See Ley et al J Agric Food Chem. 2005 Jul 27; Abstract; See PTO-892). Further GIV3727, was another compound that was known to inhibit bitter taste (See Slack et al Curr Biol. 2010 Jun 22; Abstract; See PTO-892). Additionally, Wang taught that several compounds with various structural moieties (esters (101 compounds), followed by alcohols (20 compounds) and aldehydes (28 compounds)) were responsible for discernment of flavor (includes taste and smell) of one food item such as a pear. (See Wang et al Molecules. 2019 May 9; Abstract; See PTO-892). As such identification of compounds that mask or inhibit bitter flavor is not a matter of routine selection from a known and defined class. Further, identifying which of the compounds that mask taste also provide activation adds another level of complexity requiring extensive screening, optimization, and experimentation. In the absence of guidance from the specification practicing full scope of the claimed invention would require undue experimentation.
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004)
Therefore, in light of the breadth of the instant claims, broadly drawn to use of any agent that can mask bitter taste, the lack of teachings, guidance and working examples in the specification directed to compounds masking bitter taste and activation of opsins, and particularly the lack of any example involving bitter taste masking agents, and the recognized unpredictability in the art at the time of filing, the skilled artisan would be required to perform an undue amount of experimentation to select appropriate agents and to determine the appropriate conditions necessary to carry out the methods as current claimed. Accordingly, claims 23-24 and 28 fail to satisfy the enablement requirement.
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 2-3, 15-17, 23-25 and 27-28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
Claims 2-3 and 16-17 require variants of OPN3 and/or OPN1SW. The specification doesn’t provide a clear definition of variants including what specific amino acid substitution, truncations, insertions are qualified a variants and will be encompassed by the claim. As such the metes and bounds of this claim are unclear.
Claims 15, 23-25, 27 and 28 require a “putative modulator” or “putative ligand” or “putative tastant/olfactant”. It is known that putative means unproven or supposed. As such the metes and bounds of this claim are unclear as to whether the claimed compound is a modulator or not. Additionally, the specification does not provide guidance as to a person of ordinary skill in the art to determine whether a compound is a modulator or a supposed modulator.
Claim 26 requires a modified form of a chemosensory ligand. It is unclear as to what modification is being envisioned. Modification encompasses several modifications, including stereoisomer changes, truncations, conjugations, among many others. A person of ordinary skill in the art would be unable to discern whether any compound will fall under the scope of the claim.
Claim Rejections - 35 USC § 103
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.
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.
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.
Claims 1-4, 8, 15-18, 20, 22, 25, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Vedel et al (J Biomol Screen. 2015 Aug; hereinafter "Vedel;" See PTO-892) in view of Wu et al (Am J Respir Cell Mol Biol. 2021 Jan; hereinafter "Wu;" See PTO-892) and Krymskaya et al (Am J Respir Cell Mol Biol. 2021 Jan; hereinafter "Krymskaya;" See PTO-892) as evidenced by Terakita et al (Genome Biol. 2005; hereinafter "Terakita;" See PTO-892).
Regarding claims 1, 3-4, 8 and 20: Vedel taught a “real-time Förster resonance energy transfer (FRET)–based cAMP high-throughput screening (HTS) assay for identification and characterization of Gs-coupled GPCR ligands and phosphodiesterase (PDE) inhibitors in living cells.” (See Vedel Abstract). Vedel’s assay “allowed measurement of
Gs-coupled receptor activation through quantification of the intracellular cAMP levels in live cells.” (See Vedel p. 852, col. 1, last para). Agonist activation of the β2AR (a GPCR) results in Gs-mediated adenylate cyclase activation and increased intracellular cAMP levels. Binding of cAMP to the Epac1 part of a Epac 149 biosensor induces a conformational change within the Epac1 protein, leading to an increased distance between the fluorescent proteins of FRET pair and a decreased FRET signal. (as required by calim 8) (See Vedel p. 852, col. 1, last para). For their high-throughput screening Vedel used HEK293 cells stably expressing the cAMP FRET biosensor and either endogenously or recombinantly overexpressed β-2AR. (as required by claim 4) (See Vedel, p. 851, col. 2, last para). Vedel validated their HTS model using known activators of cAMP or beta AR agonists, such as Forskolin, salbutamol, feneterol, among others (as required by claim 27) (See Vedel, Fig. 2). As such, Vedel taught a chemosensory activation detection element that is broadly applicable to all/many GPCRs. Further, the activity of the GPCR is measured by FRET read out. It is noted that FRET readout is an optical signal as required by claim 20. As such this reads on a detection element configured to generate a measurable signal in response to activation by binding of a chemical ligand. It is noted that Vedel does not explicitly teach a chemosensory opsin activation detection element as required by the claim.
Wu taught that opsin 3, a GPCR (See Wu p. 60, col .1, first para), is activated by light, and leads to Gαs signaling, leading to increased cAMP. (See Wu p. 60, col. 2, para 2). Wu explicitly taught that “the presence of a canonically light-sensing receptor in deep tissue beds suggests the presence of endogenous ligands that are able to activate the receptor without light or potential interaction with other receptors to trigger signaling cascades.” (See Wu p. 67, col. 2-3). Additionally, Krymskaya taught that
“[w]hether or not an endogenous ligand can be found, the potential exists for synthetic
ligand development of OPN3 agonists, based on structure–activity relationship studies, receptor modeling, and other creative strategies, such as those recently used to discover agonists for the proton-sensing receptor GPR68 (16), whose cognate ligand is believed to be the proton.” (See Krymskaya p. p, col. 1, 6th para).
A person of ordinary skill in the art would have been motivated to apply the cAMP based GPCR detection system of Vedel’s cAMP biosensor screening assay for identification of Gs-coupled ligands to Opsin 3 in view of the teachings of Wu and Krymskaya. Wu taught that OPN3 is a functional GPCR that signals through Gαs pathway to increase intracellular cAMP levels upon activation, thereby demonstrating that OPN3 produces a measurable signal of the same type detected in Vedel. Wu indicated that because OPN3 is expressed in tissues not exposed to light, endogenous non-light ligands or alternative activation mechanisms likely exist. Krymskaya reinforced this teachings by explaining that light-based activation may co-exist with alternative endogenous or synthetic chemical OPN3 ligands should be identified.
A person of ordinary skill in the art would have been motivated to use established GPCR screening techniques such as those taught by Vedel to identify and evaluate chemical ligands capable of activating OPN3.
Regarding claim 2 and 16: It is generally known that OPN3 and OPN1SW are GPCRs and share structural and functional features. (See evidence in Terakita p. 213.3 – p. 213.4). Accordingly, a person of ordinary skill in the art would have found it obvious to substitute one opsin for another (e.g., OPN3) in a GPCR-based screening and detection system.
Regarding claim 15, 17, 18, 22, 25 and 27: Vedel taught a cell-based GPCR assay in a HEK cell population expressing a receptor of interest and a AMP detection system (chemosensory opsin activation detection elements) and introduction of test compounds to detect generation of cAMP by FRET (a detectable signal) as indicated above. As such the method taught by Vedel reads on the claimed method and is thus obvious for the reasons stated above.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Vedel et al (J Biomol Screen. 2015 Aug; hereinafter "Vedel;" See PTO-892) in view of Wu et al (Am J Respir Cell Mol Biol. 2021 Jan; hereinafter "Wu;" See PTO-892) and Krymskaya et al (Am J Respir Cell Mol Biol. 2021 Jan; hereinafter "Krymskaya;" See PTO-892) and Kroeze et al (; hereinafter "Kroeze;" See IDS filed 12/24/2025).
Regarding claim 10: Teachings of Vedel in view of Wu and Krymskaya are set forth above. It is noted that none of the prior art taught detection of activation using an element which generates a detectable signal caused by β-arrestin recruitment to the activated chemosensory opsin.
Kroeze taught a general GPCR detection platform (PRESTO-TANGO), wherein ligand binding leads to receptor activation and β-arrestin recruitment, producing a measurable signal. In Kroeze’s system, upon activation of the GPCR by an agonist, β-arrestin is recruited to the C-terminus of the receptor. This is followed by cleavage of the GPCR fusion protein at the TEV protease site. Cleavage results in the release of the tTA transcription factor, which, after transport to the nucleus, activates transcription of the luciferase reporter gene. (See Kroeze Figure 1). As such Kroeze taught a chemosensory activation detection element, configured to generate a measurable signal in response to activation by binding of a chemical ligand. It is noted that that Kroeze did not specifically teach a chemosensory opsin activation detection element, comprising one or more chemosensory opsins as required by the claim. However, as pointed out above, Wu and Krymskaya taught that a plausibility of as of yet undiscovered ligand to certain opsins like OPN3.
As such it would have been obvious to a person of ordinary skill at the time of invention to modify the detection element of Vedel to use TANGO/PRESTO or similar assays such as those taught by Kroeze which is a standard, sensitive and high-throughput-compatible readout for β-arrestin recruitment caused by GPCR activation, making it a routine choice for detecting receptor activity. Since opsins are GPCRs, a person of ordinary skill would have expected that opsin activation could be detected via β-arrestin recruitment using known techniques, yielding predictable and measurable results.
Claim 7, 9, and 21 is rejected under 35 U.S.C. 103 as being unpatentable over Vedel et al (J Biomol Screen. 2015 Aug; hereinafter "Vedel;" See PTO-892) in view of Wu et al (Am J Respir Cell Mol Biol. 2021 Jan; hereinafter "Wu;" See PTO-892) and Krymskaya et al (Am J Respir Cell Mol Biol. 2021 Jan; hereinafter "Krymskaya;" See PTO-892) and Valentine et al (Methods Mol Biol. 2012; hereinafter "Valentine;" See PTO-892).
Regarding claim 7 and 21: Teachings of Vedel in view of Wu and Krymskaya are set forth above. It is noted that none of the prior art taught detection of activation using an element which is loaded with or expresses a calcium indicator.
Valentine taught methods to conduct high-throughput screening of stably or transiently transfected HTC4 cells expressing the individual S1P1–5 receptor subtypes (GPCRs). “The cells are grown in 96-well plates and loaded with the cell permeable fluorescent Ca2+ indicator dye Fura-2-AM. Changes in intracellular Ca2+ levels in response to S1P or test compounds are detected using a FlexStation II scanning fluorometer with integrated fluidics transfer capabilities.” (See Valentine Abstract). As such Valentine taught a method to high throughput screening of GPCRs using cells expressing a GPCR and wherein the cells can be configured to generate a measurable signal in response to activation by binding of a chemical ligand as required by the claim. As such the cells of Valentine read on the chemosensory activation detection element. It is noted that Valentine did not teach a chemosensory opsin activation detection element. However, as pointed out above, Wu and Krymskaya taught that a plausibility of as of yet undiscovered ligand to certain opsins like OPN3.
As such it would have been obvious to a person of ordinary skill at the time of invention to modify the detection element of Vedel to use intracellular Ca2+ mobilization which is a standard, sensitive and high-throughput-compatible readout for GPCR activation, making it a routine choice for detecting receptor activity. Since opsins are GPCRs, a person of ordinary skill would have expected that opsin activation could be detected via Ca2+ mobilization using known techniques, yielding predictable and measurable results.
Regarding claim 9: Teachings of Valentine are set forth above. It is noted that Valentine taught “The Gαq/11 subclass of Gα proteins is able to activate phosphoinositol phospholipase Cβ can hydrolyze phosphatidylinositol-4,5-bisphosphate (PIP2) to generate diacylglycerol and inositol-1,4,5-trisphosphate (IP3). IP3 binds endoplasmic IP3-gated Ca2+ channels, causing the release of Ca2+ from intracellular stores” (See Valentine, p. 1, para 1). Because Ca2+ is a charged ion and its intracellular flux reflects ion channel activity and membrane signaling events, calcium mobilization assays provide a well-established surrogate for detecting ion-based and electrical cellular responses in high-throughput screening systems.
Conclusion
Claim 23-24 and 28 appears free of art, but has enablement and indefiniteness issues.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633
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