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 .
Status of Claims
Claims 1-15 are pending and will be examined on the merits.
Priority
Domestic priority of provisional application 63/562,572, filed on 03/07/2024, is claimed on the Filing Receipt of 09/20/2024. Provisional application ‘572 does not disclose the subject matter encompassed by the instant claims. Therefore, the effective filing date of the claimed invention is the filing date of the 18/804,650 application, 08/14/2024.
Claim Objections
Claim 3 is objected to because of the following informalities: three of the four named receptors provide abbreviations. For consistency, Examiner requests "epidermal growth factor receptor" is given the abbreviation provided in the specification in paragraph [0039] of (EGFR). 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 15 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 15 is drawn to a method for monitoring tyrosine kinase activity using the biosensor of claim 1 and a reporter protein, wherein the reporter protein comprises a “structurally conserved protein domain is fused to the fluorescent protein and a protein domain that triggers an intracellular signaling response”. It is unclear if the claim is referring to a fusion protein comprising all three domains, or two fusion proteins, the first comprising the conserved domain and a fluorescent protein and the second comprising the conserved domain and the signaling domain. If the protein must comprise all three domains, it is unclear if the reporter fusion protein requires the domains to be organized in the specific order of conserved domain > fluorescent protein > intracellular signaling domain, or if the order does not matter. For the purposes of examination, claim 15 will be interpreted as requiring all three domains in any order.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim(s) recite(s) naturally occurring proteins. This judicial exception is not integrated into a practical application because there is no method claim in claims 1-8. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because all recited elements are naturally occurring. The following analysis is laid out in accordance with MPEP 2106:
Applicant’s claims recite a protein or a system of proteins. Therefore, the claim is directed to a composition of matter, which is one of the statutory categories of invention (Step 1: yes).
The claims are then analyzed to determine whether it is directed to any judicial exception. Claim 1 recites an engineered biosensor for monitoring receptor activity comprising a cell surface receptor and a tyrosine residue coupled to the receptor configured to be phosphorylated by the receptor when activated. Claim 1 recites a canonical receptor tyrosine kinase (RTK) with no distinct structural features from those that occur naturally (See Lemmon et al., Cell 141, June 25, 2010). Claims 2 and 3, which depend from claim 1, name existing RTKs and do not specify any distinct features. Therefore, as written, claims 1-3 are drawn to a naturally occurring product, or protein, with no distinct characteristics to set the claimed biosensor apart from existing counterparts. Thus, claims 1-3 recite a judicial exception. Similarly, claim 8 recites the nucleic acid that encodes this biosensor, and does not impart any distinct characteristics on the polynucleotide, and is thus directed to a judicial exception of a naturally occurring product.
Claim 4 recites a system comprising the engineered biosensor of claim 1, and a second protein comprising a first part that specifically interacts with the phosphorylated tyrosine of the biosensor and a second part that is a protein domain that triggers an intracellular signaling response. Again, there is no distinguishing structural feature in claim 4 that would differentiate the claimed system from a canonical signaling cascade that results from RTK activation (See Lemmon et al.). Claims 5 and 6 specify the first part as a structurally conserved protein domain; specifically, an SH2 domain, and do not specify any distinct features. Claim 7 recites the system of claim 4 further comprises a second biosensor of claim 1, orthogonal to the first. However, as disclosed in Lemmon et al., multiple orthogonal RTK signaling systems exist in nature, and therefore, as the biosensor of claim 1 is a naturally occurring product, claim 7 does not contribute any new feature to differentiate the system of claim 4 from a naturally occurring RTK-induced signaling cascade. Therefore, claims 4-7 are drawn a naturally occurring product, or protein, with no distinct characteristics to set the claimed system apart from existing counterparts, and thus recite a judicial exception.
Next, the claims as a whole are analyzed to determine whether any element, or combination of elements, is sufficient to ensure that the claim amounts to significantly more than the exception.
As explained above, claims 1-8 do not recite significantly more than a naturally occurring RTK signaling complex. Lemmon et al. review cellular signaling by receptor tyrosine kinases and disclose all components of the claimed system, including cell surface receptors configured to autophosphorylate a tyrosine residue (see Figures 1-2, section “activation of intracellular kinase domains” on pages 1121-1122), signaling proteins that interact with the phosphorylated tyrosines and trigger intracellular signaling cascades (see section” Linking RTK Activation to Cell Signaling” on pages 1122-1125 and Figure 3-4), and genes that encode these (see page 1129, left column). The instant claims do not include any distinct technical feature that contributes any markedly different characteristics from the naturally occurring proteins disclosed in Lemmon et al. Therefore, claims 1-8 are directed to a judicial exception without significantly more and are rejected under 35 USC 101.
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.
Claim(s) 1-14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Farahani et al. eLife 12:e82863, published 05/22/2023.
Claims 1-3 and 8 are drawn to an engineered biosensor for monitoring receptor activity comprising a cell surface receptor and a tyrosine residue coupled to the receptor configured to be phosphorylated by the receptor when activated. Claims 4-7 are drawn to a system comprising the engineered biosensor of claim 1, and a second protein comprising a first part that specifically interacts with the phosphorylated tyrosine of the biosensor and a second part that is a fluorescent protein or a protein domain that triggers an intracellular signaling response. Claims 9-15 are drawn to a method for monitoring RTK activity comprising measuring cell luminescence, stimulating the system of claim 4, and measuring cell luminescence a second time.
Farahani et al. disclose a biosensor comprising a cell surface receptor (specifically, the RTK EGFR; see page 3, paragraph 2, as well as Figure 1) modified with an ITAM tag that contains pairs of tyrosine residues that are phosphorylated after receptor activation, teaching the limitations of instant claims 1-3 and 8 (abstract, whole document). Farahani et al. further teach a reporter protein comprising an SH2 domain from the ZAP70 protein and an iRFP fluorescent protein, thereby teaching the additional limitations of claims 4-6. Farahani et al. further teach a second orthogonal biosensor (see page 12, Figure 5), thereby teaching claim 7. Finally, the experiments of Farahani et al. teach a method comprising measuring a first cell luminescence, system activation, and measuring a second cell luminescence, thereby teaching claim 9, as well as exposing the system to a pharmaceutical agent (EFG) and measuring luminescence and measuring the fluorescence over a period of time, teaching claims 11-12, in figures 1-5 and the corresponding text. The limitations of claims 10, 13, and 14 are addressed by the limitations of claims 3, 5, and 6. Therefore, Farahani et al. anticipates claims 1-14.
Claim(s) 1-14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tiruthani et al., Sci. Signal. 12, published 06/04/2019.
Tiruthani et al. disclose a biosensor comprising a cell surface receptor (specifically, the RTK EGFR; see abstract, page 1, right column, as well as Figures 1-4) with phosphorylation residue pTyr992, teaching the limitations of instant claims 1-3 and 8 (abstract, whole document). Tiruthani et al. further teach a reporter protein comprising an SH2 domain from the PLCy1 protein and an EGFP fluorescent protein, thereby teaching the additional limitations of claims 4-6. The experiments of Tiruthani et al. teach a method comprising measuring a first cell luminescence, system activation, and measuring a second cell luminescence, thereby teaching claim 9, as well as exposing the system to a pharmaceutical agent (sodium orthovanadate) and measuring luminescence and measuring the fluorescence over a period of time, teaching claims 11-12, in figures 1-5 and the corresponding text. The limitations of claims 10, 13, and 14 are addressed by the limitations of claims 3, 5, and 6.
Furthermore, Tiruthani et al. teach the implementation of this system in live cells. Live cells contain multiple RTKs which are activated by binding different ligands and triggering different downstream signaling pathways, as recited on page 1, left column. As all limitations of the biosensor of claim 1 are met by any RTK, the system of Tiruthani et al. inherently contains multiple orthogonal biosensors, and thus Tiruthani et al. teaches the limitations of claim 7.
Therefore, Tiruthani et al. anticipates claims 1-14.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Farahani et al. in view of Sloan-Lancaster et al., J Exp Med (1997) 186 (10): 1713–1724.
Claims 1-3 and 8 are drawn to an engineered biosensor for monitoring receptor activity comprising a cell surface receptor and a tyrosine residue coupled to the receptor configured to be phosphorylated by the receptor when activated. Claims 4-7 are drawn to a system comprising the engineered biosensor of claim 1, and a second protein comprising a first part that specifically interacts with the phosphorylated tyrosine of the biosensor and a second part that is a fluorescent protein or a protein domain that triggers an intracellular signaling response. Claims 9-15 are drawn to a method for monitoring RTK activity comprising measuring cell luminescence, stimulating the system of claim 4, and measuring cell luminescence a second time.
Farahani et al. disclose a biosensor comprising a cell surface receptor (specifically, the RTK EGFR; see page 3, paragraph 2, as well as Figure 1) modified with an ITAM tag that contains pairs of tyrosine residues that are phosphorylated after receptor activation, teaching the limitations of instant claims 1-3 and 8 (abstract, whole document). Farahani et al. further teach a reporter protein comprising an SH2 domain from the ZAP70 protein and an iRFP fluorescent protein, thereby teaching the additional limitations of claims 4-6. Farahani et al. further teach a second orthogonal biosensor (see page 12, Figure 5), thereby teaching claim 7. Finally, the experiments of Farahani et al. teach a method comprising measuring a first cell luminescence, system activation, and measuring a second cell luminescence, thereby teaching claim 9, as well as exposing the system to a pharmaceutical agent (EFG) and measuring luminescence and measuring the fluorescence over a period of time, teaching claims 11-12, in figures 1-5 and the corresponding text. The limitations of claims 10, 13, and 14 are addressed by the limitations of claims 3, 5, and 6 as set forth above.
Farahani et al. do not teach the limitations of claim 15. Claim 15 is drawn to a method for monitoring tyrosine kinase activity using the biosensor of claim 1 and a reporter protein, wherein the reporter protein comprises a “structurally conserved protein domain is fused to the fluorescent protein and a protein domain that triggers an intracellular signaling response”.
Sloan-Lancaster et al. teach the fusion of a GFP coding sequence to the C-terminus of ZAP-70 kinase (abstract, page 1715, Fig. 1). The signaling capabilities of ZAP70 are intact. Therefore, it is possible to fuse a fluorescent protein to a fully intact version of ZAP70 able to initialize signaling cascades within a cell. The tagged protein of Sloan-Lancaster et al. would function similarly to the protein of Farahani et al. as they have the same structurally conserved protein domain that would interact with the biosensor of claim 1. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that a claim would have been obvious if the substitution of one known element for another yields predictable results to one of ordinary skill in the art. It would be obvious to apply the reporter protein containing GFP and the conserved domain of ZAP70 for a reporter protein comprising GFP and the entirety of the ZAP70 protein, including the conserved domain, to be used in a known method in the art (monitoring protein localization) to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary. Therefore, the combination of Farahani et al. in view of Sloan-Lancaster et al. renders instant claims 1-15 obvious.
Claim(s) 1-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tiruthani et al. in view of Millarte et al. (2015) Molecular biology of the cell, 26(12), 2263-2278..
Tiruthani et al. disclose a biosensor comprising a cell surface receptor (specifically, the RTK EGFR; see abstract, page 1, right column, as well as Figures 1-4) with phosphorylation residue pTyr992, teaching the limitations of instant claims 1-3 and 8 (abstract, whole document). Tiruthani et al. further teach a reporter protein comprising an SH2 domain from the PLCy1 protein and an EGFP fluorescent protein, thereby teaching the additional limitations of claims 4-6. The experiments of Tiruthani et al. teach a method comprising measuring a first cell luminescence, system activation, and measuring a second cell luminescence, thereby teaching claim 9, as well as exposing the system to a pharmaceutical agent (sodium orthovanadate) and measuring luminescence and measuring the fluorescence over a period of time, teaching claims 11-12, in figures 1-5 and the corresponding text. The limitations of claims 10, 13, and 14 are addressed by the limitations of claims 3, 5, and 6 as set forth above.
Furthermore, Tiruthani et al. teach the implementation of this system in live cells. Live cells contain multiple RTKs which are activated by binding different ligands and triggering different downstream signaling pathways, as recited on page 1, left column. As all limitations of the biosensor of claim 1 are met by any RTK, the system of Tiruthani et al. inherently contains multiple orthogonal biosensors, and thus Tiruthani et al. teaches the limitations of claim 7.
Tiruthani et al. do not teach a method for monitoring RTK activity wherein the reporter protein comprises a “structurally conserved protein domain is fused to the fluorescent protein and a protein domain that triggers an intracellular signaling response”.
Millarte et al. teach PLCy1 tagged with a GFP construct (see page 2267, left column, and Figure 4). The signaling capabilities of PLCy1 are intact. Therefore, it is possible to fuse a fluorescent protein to a fully intact version of PLCy1 able to initialize signaling cascades within a cell. The tagged protein of Millarte et al. would function similarly to the protein of Tiruthani et al. as they have the same structurally conserved protein domain that would interact with the biosensor of claim 1. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that a claim would have been obvious if the substitution of one known element for another yields predictable results to one of ordinary skill in the art. It would be obvious to apply the reporter protein containing GFP and the conserved domain of PLCy1 for a reporter protein comprising GFP and the entirety of the PLCy1 protein, including the conserved domain, to be used in a known method in the art (monitoring protein localization) to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary. Therefore, the combination of Tiruthani et al. in view of Millarte et al. renders instant claims 1-15 obvious.
Conclusion
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/AMELIA STEPHENS/Examiner, Art Unit 1645
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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