DETAILED ACTION
The Examiner of record has changed.
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 claims priority to PCT/US2019/065226 with a filing date of 12/10/2018.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 11/22/2024 was acknowledged. Further, Applicant’s election without traverse of species from groups 1, 3 and 4 in the reply filed on 11/22/2024 was acknowledged. Applicant's election with traverse of the following species from groups 2 and 5 in the reply filed on 11/22/2024 was also acknowledged. Further, the traversal was not found persuasive.
The requirement is still deemed proper and is therefore made FINAL.
Amendments and Arguments
This action is in response to papers filed 16th Jul 2026, in which no claims were amended, no claims were canceled, and no new claims were added.
Applicant’s arguments, also filed 16th Jul 2026, with respect to:
rejections of claims under 35 USC § 102 and 103 have been fully considered but are not persuasive for the reasons discussed in this office action. The 35 USC § 102 rejection is maintained.
In addition, a new 35 USC § 112 and 103 rejection is made in this Office Action, not necessitated by amendments.
Rejections not reiterated here are withdrawn.
Status of Claims
Claims 1-2,5-6,9-12,14,17,20,24,28,31-34,42 and 105-109 are currently under examination due to applicants election of Group I in the response to the Requirement for Restriction/Election. Claims 44, 55, 59, 68, 81, 88, 100 and 103 are withdrawn.
New Claim Rejections - 35 USC § 112 not necessitated by amendment
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 1-2,5-6,9-12,14,17,20,24,28,31-34,42 and 105-109 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 claim 1, the phrase "(ii) … a second fusion protein comprising a second protein which interacts with the first protein upon activation of the first protein and a protease or a fragment thereof capable of cleaving the protease cleavage site within the first fusion protein" in claim 1 renders the claim indefinite because it is not clear if the second protein is the protease or the second protein interacts with the first protein and a protease. The specification in pg. 3, 2nd para states: In some embodiments, the second protein which interacts with the first protein upon activation of the first protein is β-arrestin, a G-protein receptor kinase (GRK), or G-alpha. In some embodiments, the second protein is β-arrestin. Then, in the same para goes on to state: In some embodiments, the protease is a Tobacco Etch Virus nuclear inclusion A protease (TEV protease).Thus, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention, particularly, what is the composition of the second protein.
Clarification is required.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
In the interest of compact prosecution, the second protein will be interpreted as “comprising a protease”.
Written Description
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 1-2, 5-6, 9-10, 11-12, 14, 17, 20, 24, 28, 31-34, 42, and 105-109 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.
The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997).
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). 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, reduction to drawings, 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
Scope of the Invention
The preamble recites: in vivo
In the instant case, the genera are
protease (recited in claim 1)
fragment thereof (recited in claim 1)
The broadest reasonable interpretation of the scope of the genera listed above is a truncated protease that retains its proteolysis function in vivo. This interpretation is based on Fig. 1 that depicts the first step in the cascade of events that eventually enables detection is proteolytic cleavage to release a transcription factor.
Disclosure of a Complete or Partial Structure
Regarding 1) protease, Applicant describes β -arrestin-Tobacco Etch Virus nuclear inclusion A protease (Barr-TEV) fusion protein (Fig. 1). Working examples: Example 1, utilizes an Expi 293T cell line was generated that stably expresses the Barr-TEV fusion protein [pg. 29], Example 2, utilizes HEK293 cell line that stably expresses the Barr-TEV fusion protein and luciferase [pg. 30]. Examples 6-7 and 9 [pgs. 158-159, 161] utilize the same protease as in Examples 1/2. The inventive concept requires a protease to drive expression of a barcode [Summary of Invention]. There are no other proteases described, and there is no in vivo description.
Regarding 2) fragment thereof, there is no description of this limitation.
Species Not Described
No in vivo description is described.
No fragment thereof (of a protease) either in vitro or in vivo is described.
Structure/Function Correlation
Regarding the genera, as discussed above, Applicant’s claims encompasses proteins/peptides with the proviso that they will cleave and turn on a cascade of events [Summary of Invention], while only one particular fusion protein is described in the instant specification without any correlation to what core sequence is encompassed by the recited protease/fragments. The breadth of the claimed genera is enormously broad with an unfathomable number of structurally divergent and diverse proteins/fragments.
The functional characteristic is not coupled with a known structure.
The Spec. does not identify a core structure necessary for being a functional protease/ fragment of a protease. Among the evidences provided for a protease/fragment that will function as intended in vivo, no core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for activation of the cascade of events is disclosed in such a way to demonstrate possession of the full invention as claimed at time of filing.
Knowledge from the State of the Art
The art teaches that it is essential to know the nature/structure of the protease/fragment used to practice the invention in vivo, as recited. For example, Guo (Guo, C.J., Chang, F.Y., Wyche, T.P., Backus, K.M., Acker, T.M., Funabashi, M., Taketani, M., Donia, M.S., Nayfach, S., Pollard, K.S., et al. (2017). Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases. Cell 168, 517-526 e518.) uncovered that a common gut bacterial cluster produces a reactive peptide aldehyde that inhibits specific host proteases. See eTOC Fig. on pg. 3 and Fig. 3. One biologically active species is a peptide aldehyde released during biosynthesis, which has potent protease inhibitory activity. Thus, one would not be able to use any protease or fragment of any protease, without consideration of the microenvironment, such as in vivo, as recited.
Dependent Claims
Claims 2,5-6,9-12,14,17,20,24,28,31-34,42 and 105-109 do not further limit the genus of nucleic acid molecules so as to resolve the issues above, and are therefore, not sufficiently described for at least the reasons above.
Conclusion of Written Description
Therefore, the examiner concludes there is insufficient written description support for the instantly claimed genera of proteases/fragment as recited. Only a fusion protein of β-arrestin-TEV protease as the protease used in in vitro but not the full breadth of the claims is supported by Applicant’s disclosure.
Maintained Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2, 5-6, 9-10, 11-12, 14, 17, 105, 106, remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Galinski et al. (‘Multiplexed Profiling Of GPCR Activities By Combining Split TEV Assays And EXT-Based Barcoded Readout. 2018).
Regarding claim 1, Galinski discloses a method for determining if a test compound modulates an activity of a first protein (a method for determining a therapeutic drug (test compound) modulates an activity of GPCR (a first protein) in a living cell in culture (i.e., in vivo); abstract; page 7, third paragraph; page 8, ninth paragraph to page 9, second paragraph; wherein if the test compound modulates an activity of GPCR in a living cell in an ex vivo environment, then the test compound would inherently also modulate the activity of GPCR in an in vivo environment), comprising (a) contacting said compound with a cell (comprising contacting said compound with a cell; page 8, ninth paragraph to page 9, second paragraph) comprising (i) a first nucleic acid molecule which encodes a first fusion protein (comprising an entry vector (a first nucleic acid molecule) which encodes a first fusion protein; Figure 1a; page 2, second paragraph; page 8, fifth paragraph) comprising a first protein, a cleavage site for a protease, and a protein which activates transcription of a reporter gene in said cell (comprising a GPCR (a first protein), a TEV cleavage site (a cleavage site for a protease), and GAL4-VP16 transcription factor (a protein which activates transcription of a reporter gene in said cell); Figure 1a; page 2, second paragraph; page 8, fifth paragraph), (ii) a second nucleic acid molecule which encodes a second fusion protein (a second entry vector (nucleic acid molecule) which encodes a second fusion protein; Figure 1a; page 2, second paragraph; page 8, fifth paragraph) comprising a second protein which interacts with the first protein upon activation of the first protein and a protease or a fragment thereof capable of cleaving the protease cleavage site within the first fusion protein (comprising G-arrestin2 (a second protein) which interacts with GPCR (the first protein) upon activation of the first protein and a TEV protease fragment capable of cleaving the protease cleavage site within the first fusion protein; Figures 1a-b; page 2, second-third paragraphs; page 8, fifth paragraph), and (iii) a third nucleic acid molecule which comprises a reporter gene (a third entry vector (nucleic acid molecule) which comprises a reporter gene; Figure 1a; page 2, third paragraph; page 8, fifth paragraph), wherein said reporter gene is a barcode sequence operably linked to an element responsive to the protein which activates its transcription (wherein said reporter gene is a barcode sequence operably linked to an element responsive to the GV (protein with activates its transcription; Figures 1a-b; page 2, second-third paragraphs; page 8, fifth paragraph), and (b) determining the level of transcription of said barcode sequence (determining the level of transcription of said barcode sequence; Figure 1c; page 2, fourth paragraph; page 4, second paragraph; page 7, third paragraph; page 9, third-fourth paragraphs.
Regarding claim 2, Galinski teaches wherein the first nucleic acid molecule, the second nucleic acid molecule and the third nucleic acid molecule are clonally expressed to enable linkage of a specific receptor to an individual barcode (wherein the first entry vector (nucleic acid molecule), the second entry vector (nucleic acid molecule) and the third entry vector (nucleic acid molecule) are clonally expressed to enable linkage of a specific reporter to an individual barcode; Figures 1a-b; page 2, fourth paragraph; page 8, fifth paragraph).
Regarding claim 5, Galinski discloses wherein the barcode sequence comprises from 4 to 50 bases (wherein the barcode sequence comprises a EXT barcode selected from EXT01 through EXT85 which all contain 49 bases ;: Supplementary Table S2: page 2, third paragraph: page 4, second paragraph).
Regarding claim 6, Galinski et al. teaches “In a first test, we investigated the
functionality of single GPCR split TEV assays coupled to an EXT readout and compared its performance to standard luciferase readings. By monitoring only one GPCR per assay, we compared adrenergic receptor ADRA2B and serotonin receptor HTR2A activity in independent single luciferase and single EXT assays using dose-response analyses (Fig. 1c–h). For these assays, cells were transiently transfected with GPCR split TEV components and reporters, which were allowed to express for 20 h. Following to a starvation period of 18h, cells were stimulated with agonists for 6h and lysed for subsequent luciferase assays or EXT-based next-generation sequencing analysis (Supplementary Fig. S1a). For antagonistic assays, compounds were added
1h before agonist to ensure proper incubation (Supplementary Fig. S1b).” (Galinski et al, Results).
Regarding claims 9-10, Galinski et al. teaches GPCR and transmembrane proteins (Abstract).
Regarding claims 11-12, Galinski et al. teaches orphan GPCR and non-olfactory GPCR.
Regarding claim 14, Galinski et al. teaches gal4/VP16 in the results section.
Regarding claim 17, Galinski et al. teaches GRK in the second paragraph.
Regarding claim 105, Galinski et al. teaches wherein the second nucleic acid is stably expressed by the cell.
Regarding claim 106, Galinski et al. teaches in the third paragraph linking to the transcription factor via a cleavage site for Tobacco Etch Virus nuclear inclusion A protease (TEV protease), (ii) the second fusion protein comprises B-arrestin and TEV protease (Barr-TEV) fusion protein configured to cleave the TEV protease site on the first fusion protein, and (iii) the third nucleic acid molecule comprising a barcode sequence operably linked to a promoter specifically activated by the tTA transcription factor, wherein each barcode is specific for an individual GPCR.
Response to Arguments
Applicant's arguments filed 16th Jul, 2025 to anticipation of original claims under 35 USC § 102 have been fully considered but are not persuasive as discussed below. The 35 USC § 102 rejection of claim 1 and dependent claims in view of Galinski is maintained.
Further, a new 35 USC § 103 rejection of claim 1, directed to a different claim interpretation, over Galinski in view of Aper has been presented in this Office Action.
Applicants essentially assert that: 1) the claims are directed to methods comprising "a protease or a fragment thereof capable of cleaving the protease cleavage site within the first fusion protein." and make reference to paragraphs in the specification that teach this limitation; and 2) Galinski cited in the NFOA does not teach such an enzymatically active protease. Specifically, the Remarks state that Galinski requires protein complementation of two enzymatically inactive fragments of the TEV protease; in Galinski, the enzymatically inactive NTEV fragment and the artificial transcription factor GAL4-VP16 (GV) are fused to the C-terminal end of a candidate GPCR, separated from each other by a TEV cleavage site (tevS) (pg. 7, second to the last para).
The Remarks are not found persuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., an active protease) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicants may consider amending the claims to recite consisting of an active protease, to overcome this rejection.
As discussed in the current 103 rejection below, the same reference of Galinski is relied upon as in the previous office action for independent claims. However, new references have been applied to the independent claim that are directed to an active protease, thus rendering the same limitation obvious for reasons set forth above.
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.
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(s) 1-2, 5-6, 9-10, 11-12, 14, 17, 105, 106 is/are rejected under 35 U.S.C. 103 as being unpatentable over Galinski et al. (‘Multiplexed Profiling Of GPCR Activities By Combining Split TEV Assays And EXT-Based Barcoded Readout. 2018), in view of Aper (ACS Synth. Biol. 2018, 7, 2216−2225). This is a new rejection not necessitated by amendment.
This rejection is directed to the following claim interpretation of claim 1:
(ii) a second nucleic acid molecule which encodes a second fusion protein comprising an active protease which interacts with the first protein upon activation of the first protein and a protease capable of cleaving the protease cleavage site within the first fusion protein.
Regarding claims 1-2, 5-6, 9-10, 11-12, 14, 17, 33, 105, 106, the teachings of Galinski et al. are above.
Regarding claim 1, further teachings of Galinski are discussed below.
With respect to the second fusion protein comprising an enzymatically active protease, Galinski teaches a split TEV system based on the complementation of two enzymatically inactive fragments of the TEV protease (NTEV and CTEV, i.e., N-terminal and C-terminal fragments of TEV, respectively; see page 2, paragraph 2 and Figures la and lb of Galinski). In the method of Galinski, complementation of the two enzymatically inactive TEV fragments is required to reconstitute the enzymatically active protease. Specifically, in Galinski, the enzymatically inactive NTEV fragment and the artificial transcription factor GAL4-VP16 (GV) are fused to the C-terminal end of a candidate GPCR, separated from each other by a TEV cleavage site (tevS) (see Figures la and lb of Galinski). The enzymatically inactive CTEV fragment is fused to truncated β-arrestin (Figure la of Galinski). After ligand-dependent GPCR activation, β-arrestin is recruited to the GPCR leading to the reconstitution of the enzymatically active TEV protease from NTEV and CTEV causing the release and translocation of GV into the nucleus, where GV binds and activates a reporter.
Galinski does not teach the second fusion protein comprising an enzymatically active protease, prior to complementation.
Aper teaches protease-mediated control of scaffold activity wherein the scaffold is a monovalent inhibitory ExoS peptide or a single bivalent ExoS peptide fused to T14-3-3 via protease-cleavable linkers (abstract, Figs. 1, 2A). The protease-activatable 14-3-3 scaffolds were successfully applied to construct a three-step signaling cascade leading to an active luciferase (Figure 3). The protease is either TEV and/or Xa (Figs. 1 and 2 legend). Another embodiment describes a fusion protein FGG-C9 (comprising the protease, caspase) as the protease (Fig. 3). Protease-activatable 14-3-3 proteins thus represent a modular platform whose properties can be rationally engineered to fit different applications, both to create artificial in vitro synthetic molecular networks. Aper suggests such protease-activatable 14-3-3 activity could be connected to other protease activatable systems (some of the protease-inducible or -inducing systems that have been engineered in recent years, including split-caspases, split-TEVs,52−54, pg. 2223, middle para). Thus, Aper’s teachings of a fusion protein comprising 14-3-3 activated by protease cleavage read on instant first fusion protein and Aper’s teachings of FGG-C9, reads on the second fusion protein comprising a protease capable of cleaving the protease cleavage site within the first fusion protein, which interacts with the first protein. Aper’s TEV/Xa/FGG-caspase-9 are enzymatically active protease which cleaves a protease cleavage site within the first fusion protein.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to have modified the disclosure of Galinski with a protease whose activation is independent of the first protein, in place of a split TEV system for evaluating an agent of compound, as disclosed by Aper. Aper teach that their system is modular and therefore, one would have reasonable expectation of success in taking just this element from Aper and using it to substitute Galinski’s complementation-based protease reconstitution. One would be motivated to do so to simplify the circuit and gain access to the choice of many proteases, well-studied in the art. See MPEP 2143 B.
Regarding claims 33 and 106, Galinski taught inactive CTEV fragment is fused to truncated β-arrestin. In Galinski’s method, β-arrestin is recruited to the GPCR leading to the reconstitution of the enzymatically active TEV protease from NTEV and CTEV, inactive NTEV fragment and the artificial transcription factor GAL4-VP16 (GV) are fused to the C-terminal end of a candidate GPCR, separated from each other by a TEV cleavage site (tevS) (see Figures la and lb of Galinski), as discussed in the 103 rejection of claim 1.
Aper taught the proteases TEV and/or Xa and the fusion protein formed with Caspase 9 as discussed in the 103 rejection of claim 1.
In the rejection of claim 1, the second fusion protein comprising the protease of instant invention was made obvious by substituting Galinski’s complementation based TEV protease parts with Aper’s protease. Such substitution did not include β-arrestin as a fusion partner with the TEV.
However, Galinski further teaches G protein-coupled receptors (GPCRs) are the largest and most investigated class of cell surface receptors (1st sentence). Galinski teaches it was known that arrestins selectively bind to active phosphorylated GPCRs, which blocked receptor interactions with G proteins by simple competition. Therefore, when GPCRs are activated by agonists, continued activation (desensitization) halts when arrestins bind the GPCRs. Arrestin binding then turns on its own signaling (introduction). See pertinent recitation from pg. 7, 2nd to last para of Galinski regarding the role of arrestin in a GPCR assay:
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It would have been obvious to a person of ordinary skill in the art at the time the invention was made to have modified the disclosure of Galinski with a fusion protease whose fusion partner is β-arrestin for evaluating an agent of compound, as disclosed by Galinski. Galinski taught the benefits of including β-arrestin in a GPCR detection assay and Aper taught a TEV-fusion protein and therefore, one would have reasonable expectation of success in substituting Aper’s fusion partner for β-arrestin for the beneficial advantages disclosed by Galinski that were well-known in the art. One would have had reasonable expectation of success in carrying out the substitution because each of the components were well-known in the art and in combination, the components would be performing the same role that they were performing in the prior art. See MPEP 2144 II and 2143 B.
Thus, Galinski in view of Aper make obvious instant claims 1, 33 and 106.
Regarding claims 2, 5-6, 9-10, 11-12, 14, 17, and 105, the teachings of Galinski in the 102 section are similarly applied.
Thus, Galinski in view of Aper also make obvious instant claims 2, 5-6, 9-10, 11-12, 14, 17, and 105-106.
Claim(s) 20, 24, 31-32, 34, 107-109 is/are rejected under 35 U.S.C. 103 as being unpatentable over Galinski et al. (‘Multiplexed Profiling Of GPCR Activities By Combining Split TEV Assays And EXT-Based Barcoded Readout. 2018), in view of Aper (ACS Synth. Biol. 2018, 7, 2216−2225) as applied to claims 1-2, 5-6, 9-10, 11-12, 14, 17, 33, 105, 106 above, and further in view of Donald et al., (WO2002016940A2). Claim 34 is evidenced by Inglese (Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, Austin CP. Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11473-8.).
This is a new rejection not necessitated by amendment.
Regarding claims 20, 24, 31-32, 34, 107-109 the teachings of Galinski and Aper are above.
Regarding claims 20, 24, and 31-32, neither Galinski et al. nor Aper teach a non-adherent mammalian cell (claim 20), a test compound contained within a microbiota of a subject (claim 24), an untreated cell (claim 31), or a cell treated with a single dose of an agonist of the first protein in combination with an antagonist of the first protein (claim 32), and high-throughput formatting (claims 31 and 32).
Regarding claims 20, 24, and 31-32, Donald et al. teaches a microbial metabolite compound (a metabolite from a bacterium (a microbial metabolite compound); page 4, line 11; page 68, lines 22-25); a method of preventing or treating a disease or disorder in a subject (a method of preventing or treating a disease or disorder in a subject; page 3, lines 15-26; page 4, lines 11-16), the method comprising administering one or more antibiotics effective to target a bacterial strain (the method comprising administering one or more antibiotics effective to target a bacterial strain; page 3, lines 15-26; page 4, lines 11-16) comprising a nucleic acid sequence encoding a metabolite producing gene (comprising molecular targets including proteins or mRNA coding for proteins associated with metabolites (comprising a nucleic acid sequence encoding a metabolite production gene); page 3, lines 15-26, page 68, lines 22-25); a method for evaluating potential effectiveness of an agent or treatment (a method for evaluating potential effectiveness of an agent or treatment; page 54, lines 5-15). In microarray preparation §3.2.1, Donald teach, it is also possible to use cDNA from a single cell, and compare, for example, the absolute amount of a particular mRNA in, e.g., a drug-treated or pathway-perturbed cell and an untreated cell.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to have modified the disclosure of Galinski to have included steps for evaluating an agent which is amicrobial metabolite, as disclosed by Donald et al., the steps comprising introducing a nucleic acid probe or other reagent capable of binding specifically to a nucleotide expressed by a bacterial strain in order to enable the determination of the expression of metabolite producing genes as a means of determining the effects of the therapeutic agent or compound on the genes responsible for metabolite production, as well as direct measurement of metabolite production, to better and more accurately determine the efficacy of the compound.
Regarding the limitation of high-throughput format as recited in claims 31, 32, 107-109, Donald teaches the method as discussed above in a high throughput format (abstract).
Regarding claim 34, Inglese evidences that administering a combination of an agonist and an antagonist in an assay is a well-known pharmacological strategy used to probe receptor function, ligand interactions, and signaling mechanisms. See abstract and introductory paragraph. Inglese teaches the same in a high-throughput format. See Inglese, fig. 1 where concentration response curves with inhibitory (blue) or stimulatory (red) activity are graphed.
Thus, Galinski and Aper in view of Donald make obvious instant claims 20, 24, 31-32, 34, 107-109.
Claim(s) 28 and 42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Galinski et al. (‘Multiplexed Profiling Of GPCR Activities By Combining Split TEV Assays And EXT-Based Barcoded Readout. 2018), in view of Aper (ACS Synth. Biol. 2018, 7, 2216−2225) and in view of Donald et al., (WO2002016940A2), Claim 34 is evidenced by Inglese (Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, Austin CP. Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11473-8.) as applied to claims 20, 24, 31-32, 34, 107-109 above, further in view of Antti (WO 2011/064000 A1).
This is a new rejection not necessitated by amendment.
Regarding claims 28 and 42, neither Galinski et al., Aper, nor Donald teach identifying a bacterial strain or taxon which produces said test compound within said microbiota.
However, before the effective filing date of instant invention, Antti had taught methods for monitoring, identifying or diagnosing an infection in an individual, by assessing the metabolites produced and thus also identifying the bacterial strain (abstract, Table 1 on page 21 where the columns are microbe ID and the rows are different metabolites). The detection of metabolites is followed by analyzing the metabolite composition of said sample to determine a test metabolite profile of said sample, and comparing said test metabolite profile with a control metabolite profile. identity of metabolites was detected by corelating with NIST database (abstract, pg. 29). Antti’s method is advantageous as a method for assessing the efficacy of a treatment of an infection (abstract)..
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to have modified the disclosure of Galinski et al., Aper, and Donald to have included a method of determining the identity of the bacterial strain that produced the metabolite, as disclosed by Antti. The knowledge of the identity of the involved bacteria would be advantageous to guide further treatment. One would have had reasonable expectation of success in making the combination because in combination, each element would merely be performing the same function as it does separately. Identifying the bacteria following the combination of methods would have lead to predictable success because Antti provide the details of the method and apparatus and a computer-usable medium configured to perform said methods. See MPEP 2144 II and 2143 B.
Regarding claim 42, the inclusion of limitations taught by Galinski et al., Aper, Donald and Antti into a single method as discussed above, would result in the method recited in claim 42.
Thus, Galinski et al., Aper, and Donald in view of Antti make obvious instant claims 28 and 42.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant's arguments filed 16th Jul, 2025 to obviousness rejection of original claims under 35 USC § 103 have been fully considered but are not persuasive.
Applicants argue:
Galinski does not teach an active protease.
This has been addressed in the response to 102 rejection.
unexpected and superior advantages over the method of Galinski.
In view of new claim interpretation, a 35 USC § 103 rejection of claims 20, 24, 28, 31-34, 42, 107-109 in view of Galinski and others is made. Since Instant Office Action relies on Galinski in view of Aper and further in view of Donald, any unexpected and superior advantages of instant invention must be compared with the combined references of Galinski, Aper, and Donald.
Applicants arguments are not dispositive. A new §103 rejection is made.
Relevant Prior Art Not relied Upon
The following art is made note of and not currently relied on, but is relevant to applicants invention. Kosuri et al (US 2020/0255844 A1, claiming priority to Provisional application No. 62 / 528,833, filed on Jul .5 , 2017) have taught a Scalable, Multiplexed Assay for Decoding Receptor-Ligand Interactions wherein expression of a barcode identifies receptor activation. Working examples include GPCRs that turn on cAMP signaling in HEK293T cells. DNA barcodes are included in the 3 ' UTR of the reporter gene that uniquely associate with one receptor in the library expressed on the same plasmid. The relative abundance of each barcode is plotted into a heat map displaying affinity of the odors for each receptor .
The closest prior art is applied above.
CONCLUSION
No claims are allowed.
Correspondence
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/ Examiner, Art Unit 1635
/CATHERINE KONOPKA/ Primary Examiner, Art Unit 1635
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