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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/12/2025 has been entered.
Status of Claims
Claims 1-6, 10-12, 15-16, 18-20, 22, 24-27 and 33 are pending in the application. Claims 24-27 and 33 are presently withdrawn. Claims 1, 16, 24 and 33 have been amended without adding new matter. Accordingly, claims 1-6, 10-12, 15-16, 18-20 and 22 presently considered.
Election/Restrictions
Applicant’s election of Group I in the reply filed on 08/29/2024 remains in effect.
Claims 24-27 and 33 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/29/2024.
Withdrawn
Rejection of claim 1 under 35 U.S.C. 112(b) is withdrawn in light of the amendments.
Maintained Rejections and New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
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.
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.
Claims 1-6, 10-11 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Nivala (US 20160032236 A1; previously cited) and further in view of Li et al. (US 20180080072 A1; previously cited), hereafter “Li”.
Regarding claim 1, Nivala teaches a device and method for translocating a protein through a nanopore while monitoring electronic changes caused by different amino acids in the protein (see Abstract). Nivala teaches that translocation of proteins through a nanopore (sensor)
offers a number of possible applications, including sequencing, structure/fold analysis, purification/separation, intracellular protein delivery, and insight into the mechanics of enzymes driving the translocating polypeptide (see pg. 5, para. [0061]). Nivala teaches an engineered protein “S2-35” used for translocation through a nanopore system having the following structure (see page 11, para. [0127]):
C-terminus>charged flexible tail>Smt3>flexible linker>Smt3>N-terminus
Nivala also teaches the engineered protein “S1” having the following structure (see pg. 11, para. [0127]):
C-terminus>charged flexible tail>Smt3>N-terminus
Nivala’s engineered proteins are also shown in Fig. 1C:
PNG
media_image1.png
484
259
media_image1.png
Greyscale
Nivala teaches the engineered Smt3 protein (the folded domains in FIG. 1C above) was modified to facilitate nanopore analysis, wherein the protein is appended with a charged, flexible glycine/serine tail, or “polyanion”, that includes 13 interspersed negatively charged aspartate residues designed to promote capture and retention of the protein in the electric field across the nanopore (see pg. 10, para. [0118]; pg. 11, para. [0121]). Nivala teaches the charged flexible tail to be drawn to the positive side of the chamber by voltage gradient (see pg. 2, para. [0020]). Hence, the charged flexible tail is understood to have a net negative charge and satisfies the limitation of “a flexible tail domain”.
According to the instant specification (see pg. 11, lines 14-16) and in view of the instant claims (i.e., claims 5-6), SUMO-like protein Smt3 satisfies the limitation of a “blocking domain”. In regards to the limitation that the blocking domain has a “stably folded tertiary structure”, Nivala teaches that the nanopore is too narrow to permit passage of a folded protein (see pg. 7, para. [0081]) and both tertiary and secondary structures must be unfolded to allow the protein to thread through the nanopore sensor in single file order (see pg. 1, para. [0008]). Nivala teaches that at the point the charged, flexible tail is threaded through the nanopore, the folded Smt3 domain prevents complete translocation of the captured protein (see pg. 3, para. [0040], lines 24-27) as the folded Smt3 domain is predicted to sit on top of the nanopore vestibule (see pg. 11, para. [0121]). Hence, it is understood that the Smt3 domain has a stably folded tertiary structure in order to prevent translocation of the protein through the nanopore.
Regarding the limitation of a “flexible analyte domain”, Nivala teaches that “as a test” the above protein was engineered to include a linker in between two Smt3 domains at the N-terminus coupled to the charged flexible segment at its C-terminus (see pg. 10, para. [0118]; pg. 11, para. [0127]). Nivala teaches these artificial linkers show different current amplitudes and duration, and one may correlate observed changes in amplitude and RMS noise to the amino acid-dependent features of the translocated protein, including its amino acid sequence and post-translational modifications (see pg. 8, para. [0090]). According to the instant specification, the flexible analyte domain is a “variable region” (see pg. 20, lines 2-3) in which the system detects an ion current pattern associated with a structural characteristic of the flexible analyte domain when it is in the tunnel of the nanopore (see pg. 24, lines 14-17). Hence, as Nivala teaches the flexible linker domain to be a sequence which can be identified and measured in the same manner, it satisfies the limitation of a “flexible analyte domain”.
Nivala does not explicitly teach wherein the flexible analyte domain is contiguous with the flexible tail domain, or separated from the flexible tail domain by an intervening linker domain.
The reason the flexible linker (“flexible analyte domain”) is not contiguous with the charged flexible tail (“flexible tail domain”) in Nivala’s S2-35, is because the protein comprises a second (intervening) Smt3 domain between the analyte domain and the tail domain, as shown above. This is because the nanopore taught by Nivala is dependent on an unfoldase, ClpX, which catalyzes unfolding of the Smt3 domains, facilitating translocation of the captured protein through the nanopore (see pg. 3, para. [0040]), rather than “blocking” further translocation of the captured protein. The examiner notes that the unfoldase, ClpX, is a feature of the nanopore system taught by Nivala, and is not part of the fusion proteins themselves. The examiner also notes that the “S1” protein taught by Nivala only has one N-terminal Smt3 domain, and while an analyte domain is not disclosed in S1, a skilled artisan would have envisaged variations of these engineered proteins in accordance with their desired application.
Nivala discloses that the “use of nanopores to sequence biopolymers was proposed more than a decade ago” (see pg. 1, para. [0009]), and since that time the most popular biosensing applications using nanopores have been for DNA sequencing (see pg. 1, para. [0008]). Nivala also teaches that the characteristics of the translocated protein can be determined in a manner analogous to the re-sequencing of DNA (see pg. 7, para. [0086]). Based on this disclosure, the prior art of Li is relied upon.
Li teaches methods of assaying the presence of target nucleic acid molecules comprising facilitating the flow of the sample through at least one nanopore in a membrane disposed adjacent or in proximity to an electrode that detects a current or current change upon movement of the target nucleic acid molecule through the nanopore (see Abstract). Hence, while Li’s disclosure is directed to nucleic acids, the principle of detection using nanopores is the same as Nivala’s. Further, Li teaches that the target nucleic acid molecule can have a tag coupled at a terminal end thereof that increases the dwell time of the target nucleic acid molecule in the nanopore (see Abstract). Li teaches that when using this method, the movement of the molecule through the nanopore takes a dwell time that is longer than when the molecule is not coupled to the tag (see pg. 1, para. [0005]). Li teaches the tag may be a polypeptide (see pg. 1, para. [0007]) which interacts with the nanopore to stop the flow of the target nucleic acid molecule through the nanopore (see pg. 3, para. [0038]), as shown in FIGURES 3A-3C:
PNG
media_image2.png
357
765
media_image2.png
Greyscale
FIG. 3A
PNG
media_image3.png
464
686
media_image3.png
Greyscale
FIG. 3B
PNG
media_image4.png
316
679
media_image4.png
Greyscale
FIG. 3C
Li teaches that the tag can be a protein that has a cross-sectional size that is larger than the cross-sectional size of the nanopore, preventing the attached molecule from flowing through the nanopore (see pg. 4, para. [0054]) and by measuring current or current change with time and determining dwell times, the target nucleic acid molecule can be detected in the sample (see pg. 4, para. [0053]). Li teaches that this method overcomes various limitations that are associated with nucleic acid amplification and sequence identification, because other methods may not generate sequence information rapidly enough and/or at the accuracy necessary for the intended application (see pg. 1, para. [0003]).
Examiner notes that Li teaches that the longer dwell time is indicative of the presence of the target nucleic acid molecule (see pg. 2, para. [0015]), while Nivala teaches that a change in dwell time can be used to measure the secondary structure of a protein (see pg. 7, para. [0087]). A person of ordinary skill would have recognized that the Smt3 of Nivala’s disclosure effectively blocks translocation of the engineered protein through the nanopore, and that in the absence of the ClpX-mediated mechanism, a terminal Smt3 would remain in its folded state, preventing further translocation of the protein, analogous to what is shown in FIG. 3C of Li. As an intervening Smt3 domain would have prevented the translocation of the analyte domain through the nanopore, one would have had sufficient reason to remove this second Smt3 domain.
Therefore, it would have been obvious for a person of ordinary skill to have arrived at the claimed invention by modifying the engineered protein of Nivala to have a single terminal Smt3 domain to effectively serve as a “blocking domain” during translocation, because Nivala teaches that the unfolded Smt3 domain prevents further translocation through the nanopore, as does the polypeptide tag taught by Li. One would have recognized that both references teach the linking of a polypeptide, larger than the nanopore, to a terminal region of a polymeric molecule which would be expected to stop translocation through the nanopore in order to detect and analyze the molecule while it is in the nanopore lumen. One would have immediately envisaged from Nivala’s disclosure that in the absence of ClpX-mediated unfolding, the intervening Smt3 domain of Nivala’s disclosure would need to be removed in order for the region of interest (i.e., “analyte domain”) to enter the nanopore lumen for detection. Furthermore, it is well within the ordinary skill in the art to have modified Nivala’s fusion protein by simply omitting the second Smt3 domain. One would have also been motivated to combine these teachings, because Li suggests that using such methods may produce more rapid and accurate results when using nanopore sensing to analyze polymeric molecules. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 2, Nivala teaches that the charged flexible tail is targeted to pass through a nanopore by being drawn to the positive side of the chamber by a voltage gradient (see pg. 2, para. [0020]). Nivala teaches that the nanopore is too narrow to permit passage of a folded protein (see pg. 7, para. [0081]) and both tertiary and secondary structures must be unfolded to allow the protein to thread through the nanopore sensor in single file order (see pg. 1, para. [0008]). This is why the negatively charged polyanion tail is “unstructured” (see pg. 11, para. [0121]) which is understood to mean lacking tertiary and secondary structure. Nivala teaches that at the point the charged, flexible tail is threaded through the nanopore, the folded Smt3 domain prevents complete translocation of the captured protein (see pg. 3, para. [0040], lines 24-27) as the folded Smt3 domain is predicted to sit on top of the nanopore vestibule (see pg. 11, para. [0121]). Hence, in view of Nivala’s teachings, it is understood that the tertiary structure of the folded Smt3 (i.e., “blocking domain”) exceeds the diameter of the nanopore which prevents further translocation of the engineered protein.
Regarding claim 3, Nivala teaches that the nanopores can have a diameter of 1.5 nm (see pg. 4, para. [0045]). As discussed regarding claim 2, it is understood from Nivala’s disclosure that the nanopore is too narrow to permit the passage of Smt3 in its folded state and that its tertiary structure must have a diameter greater than the nanopore in order for it to sit on top of the nanopore vestibule and prevent further translocation of the protein. The relative size of the unstructured tail, which is narrow enough to be threaded through the nanopore, and the folded Smt3 can also be seen in Figure 1C of Nivala. Hence, Nivala teaches the tertiary structure of Smt3 (i.e., the “blocking domain”) to have a diameter greater than the nanopore, which includes nanopores having a diameter of 1.5 nm.
Regarding claim 4, Nivala teaches the Smt3 domain is comprised of about 100 amino acids (see pg. 10, para. [0119]).
Regarding claim 5, as discussed above, Nivala teaches an N-terminal Smt3 domain which satisfies the limitation of a SUMO-like protein domain.
Regarding claim 6, as discussed above, Nivala teaches an N-terminal Smt3 domain.
Regarding claim 10, Nivala does not teach the flexible analyte domain has an amino acid sequence of between 15 and 25 amino acids. Instead, Nivala teaches the flexible linker (i.e., “flexible analyte domain”) to be 35 amino acid residues in length (see pg. 10, para. [0118], “S2-35”). Examiner notes that Nivala teaches nanopore sensing can be used to measure numerous characteristics of a protein, including its length, secondary characteristics, and modifications (see pg. 7, para. [0083]).
In view of the instant specification, “SEQ ID NO: 30 is an exemplary analyte domain sequence” (pg. 13, lines 12-14); however, this sequence is 31 amino acids in length (see instant Sequence Listing File) which is the same length as the analyte domain used in Applicant’s examples (see Table 1 on pgs. 31-33) and is also 20% higher than the upper limit of the claimed range. The instant specification also states that in some embodiments the analyte domain comprises “about 1 amino acid to about 30 amino acids” (see pg. 12, lines 10-11).
Furthermore, there is no apparent support showing the criticality of the claimed range. There is zero discussion in the present disclosure as to what considerations are taken into account when selecting a flexible analyte domain of, for example, 1 amino acid as opposed to 31 amino acids, and there is no evidence of unexpected results presented in Applicant’s disclosure using the claimed range. Furthermore, a person of ordinary skill would have recognized from Nivala and Li that nanopore analysis could be used to analyze molecules of various lengths and sizes and would have had a reasonable expectation of success in detecting a protein domain of 15 to 25 amino acids. One would have been motivated to do so, because Nivala teaches that the translocation of proteins through a nanopore offers a number of possible applications and can be used to measure a number of different protein characteristics, including sequence length, secondary structures, and modifications, which would be expected to vary amongst proteins of interest and their respective domains. See MPEP 2144.05(II)(B) which states that “[w]hen there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill”. Hence, in the absence of any evidence to show the claimed range is critical, the further limitation of claim 10 would have been obvious.
Regarding claim 11, according to the instant specification, the term “identifiable barcode” refers to the ability to detect and differentiate a particular unique barcode sequence in relation to different barcode sequences in other analyte domains using, e.g., a nanopore detection platform (see pg. 12, lines 23-27). The instant specification states that the barcode is a region of the protein that is held within the sensitive region of the nanopore lumen upon which the changes to the barcode sequence manifest changes to the nanopore ionic current signal (see pg. 4, lines 12-14).
Nivala teaches the method and device may involve measuring several characteristics of the protein including the identity of the protein (see pg. 7, para. [0083]). Nivala teaches the identity of the protein may be measured by measuring the sequence of the protein itself or by measuring the presence of a particular motif in the protein (see pg. 7, para. [0085]). In Nivala’s examples, Nivala teaches that the differences in levels of current measured between two engineered proteins containing two different linker regions during translocation was due to differences in linker amino acid composition (see pg. 12, para. [0135]). Nivala teaches that the amino acid sequence may be read in blocks of amino acids, which need not resolve each individual amino acid, but rather one could just resolve “words” or blocks/chunks of amino acids that still enable identification of the protein/polypeptide sequence (see pg. 7, para. [0086]). Hence, Nivala teaches fusion proteins containing amino acid sequences (e.g., in the flexible linker region of Nivala’s exemplified fusion proteins) that can be measured to identify the engineered protein (e.g., like a barcode). Accordingly, this disclosure meets the limitation of “an amino acid sequence containing a uniquely identifiable barcode”.
Regarding claim 12, Nivala teaches the method may involve measuring whether or not the protein is modified (see pg. 7, para. [0083]) and preferably comprises determining whether or not the protein is modified by methylation, phosphorylation, oxidation, or glycosylation (see pg. 7, para. [0088]). Nivala teaches that the artificial linkers used in the examples showed different current amplitudes and duration which may be correlated to post-translational modifications (see pg. 8, para. [0090]) which can also be determined using one or more labels, tags or spacers (see pg. 7, para. [0088]).
In view of the instant specification, exemplary post-translation modifications to be targeted include phosphorylation (see pg. 13, lines 5-12), and the analyte domain may contain a casein II (CKII) domain based on the motif “SXXD”, which can result in phosphorylation of the serine in the motif (see pg. 7, para. 12-14).
Nivala teaches a fusion protein, as described regarding claim 1, wherein the artificial linker comprises the following sequence (see pg. 11, para. [0123]) which has this motif (underlined and in bold):
GGSGSAGSGASGSSGSEGSGASGSAGSGSAGSRGSGASGSAGSGSAGSGGAEAAKEAAKEAAKEAAKEAAKAGGSGSAGSAGSASSGSDGSGASGSAGSGSAGSKGSGASGSAGSGSSGS
Hence, Nivala teaches the fusion protein wherein the flexible linker domain (i.e., “flexible analyte domain”) contains a target sequence for a post-translation modification.
Regarding claim 15, Nivala teaches the charged flexible tail domain to be 65 amino acids long (see pg. 10, para. [0118]; pg. 11, para. [0121]).
Regarding claim 16, Nivala teaches the 65-amino-acid-long, charged tail to be comprised of glycine/serine residues with 13 interspersed aspartate residues (pg. 11, para. [0121])
Claims 18-20 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Nivala and Li, as applied to claims 1-6, 10-11 and 15-16 above, and further in view Le (previously cited).
Regarding claim 18, as discussed above, Nivala teaches a fusion protein comprising, in order, an Smt3 (“blocking”) domain, a flexible linker (“analyte”) domain, and a flexible, negatively charged tail domain.
Nivala does not teach the fusion protein further comprising a secretion domain functional in a cell type of interest.
Le teaches that Escherichia coli is one of the most extensively used prokaryotic organisms for the industrial production of enzymes (see pg. 1, col. 1, para. 1), but it is a common problem that some recombinant proteins will aggregate to form inclusion bodies and only a small proportion of the protein produced is soluble and active (see pg. 1, col. 1, para. 2). Le teaches that many attempts have been made to improve the soluble expression of recombinant proteins in E. coli and the formation of inclusion bodies could be decreased by fusing the target gene to another gene (see pg. 1, col. 2, para. 1). Le teaches OsmY has been used as a fusion partner to excrete target proteins into the medium, and when fused to OsmY, E. coli alkaline phosphatase, Bacillus subtilis a-amylase, and human leptin could be secreted into the medium at high levels (see pg. 1, col. 2, para. 2). Le reports the fusion of the xynA enzyme with the protein OsmY, and the finding that cells harboring the recombinant plasmid pET-OsmY-xynA expressed an activity level about 24 times higher than that expressed from pET-20b-xynA (see Abstract).
It would have been obvious at the time of filing for a person of ordinary skill to have combined the teachings of Nivala and Le to fuse the secretion domain taught by Le to the fusion protein taught by Nivala for expression in E. coli cells, because Le teaches that fusion with OsmY results in high levels of expression using other proteins. One would have recognized that in order to apply the teachings of Nivala, a supply of the proteins being studied may be required in order to utilize the proteins and study their characteristics using a nanopore system. One would have been motivated to select OsmY, because addition of the OsmY signal sequence for secretion of the fusion protein would allow for high levels of production of the protein in soluble form, thus providing a better means for producing the fusion proteins and a good supply for applications using a nanopore system. As Le teaches fusions of an OsmY domain have been successful using several other proteins, one would have recognized the results of the combination to be predictable. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103). Furthermore, it is well within the ordinary skill in the art to design and make fusion proteins using peptides of known structure and function for secretion in E. coli cells.
Regarding claim 19, Le teaches the fusion protein was designed to carry an N-terminal OsmY signal sequence (see pg. 2, col. 2, para. 1).
Regarding claim 20, Le teaches the overexpression of a soluble fusion protein in E.coli using OsmY as a fusion partner (see pg. 1, col. 2, para. 3). As discussed above, E. coli is a prokaryotic organism and, hence, satisfies the limitation of a “prokaryotic cell”.
Regarding claim 22, Le teaches the fusion of OsmY to recombinant proteins to improve their soluble expression in E. coli, as discussed above.
Response to Arguments
Regarding the rejections under 35 U.S.C. 103, Applicant argues that the alleged modifications to Nivala would render Nivala unsuitable for the purposes described, because Nivala’s artificial linkers do not provide different current amplitudes and durations in the absence of unfoldase. Applicant presents evidence from Nivala (paras. [0090] and [0124]) to show that Nivala used a current pattern in “state (iii)” to correlate protein structure, which was not observed when ClpX and ATP were absent. In view of this, Applicant argues, a person having ordinary skill in the art would not have had a reasonable expectation of success in the alleged modifications of the references. Applicant further argues that the alleged modifications to Nivala would not be reasonably expected to result in the claimed fusion reporter protein.
Applicant’s arguments have been fully considered but they are not persuasive for the following reasons.
(1) In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, one would have recognized from Nivala’s disclosure that the presence of an intervening Smt3 domain would prevent translocation of Nivala’s flexible linkers in the absence of ClpX and ATP. As discussed in the present rejection, a person of skill would have recognized that this additional Smt3 would not be required and could be excluded in order to allow for translocation and detection of the analyte region when using a nanopore system that does not feature ClpX and ATP. Furthermore, the prior art of Li demonstrates the proof-of-concept of using a bulky (folded) terminal protein to increase dwell time in a nanopore, which Li suggests may provide more rapid and accurate results.
(2) In response to applicant's argument that “the alleged modifications to Nivala would not be reasonably expected to result in the claimed fusion reporter protein”, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, the combination of Nivala and Li would have reasonably suggested to a person of skill that polymeric molecules possessing a large, terminal polypeptide “tag”, larger than the opening of a nanopore, would be useful to increase dwell time when conducting nanopore analysis. Furthermore, it would have been prima facie obvious to have used the Smt3 taught by Nivala, because Nivala teaches this protein to already possess this structure and function and to already be present at the N-terminus of Nivala’s exemplified fusion proteins.
Applicant further argues that Nivala in view of Li and/or Le fail to render obvious the claimed fusion reporter proteins. First, it is not at all clear why a person would have been motivated to modify Nivala’s system “for translocating a protein through a nanopore” (claim 1) so that it would be incapable of translocating a protein through a nanopore, other than because of a hindsight reconstruction of the present claims. Second, even if there was a motivation to modify a device for translocating a protein into a device where proteins are blocked from translocating, there is no reasonable expectation of success that such a modification would result in the present fusion reporter protein.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, Nivala and Li clearly teach polypeptides attached to polymeric molecules for nanopore analysis, wherein the attached polypeptides (Smt3 or “tag”) block further translocation after the molecules enter the nanopore. Li suggests that using such methods may produce more rapid and accurate results when using nanopore sensing, and Nivala teaches that the use of nanopores to identify structural features in a protein are analogous to previous methods using nucleic acids. Accordingly, a person of skill would have been motivated to combine these teachings. As discussed in the present rejection, a person of skill would have recognized that the additional (intervening) Smt3 could be excluded in order to allow for translocation, and the terminal Smt3 would then function in the manner disclosed by Li. Thus, in contrast to the allegation that the protein would be “incapable of translocating”, a person of skill would have recognized there to be a reasonable expectation of success.
Applicant further argues that Li relates to detection of nucleic acid molecules using nanopores and tags, and does not address or suggest protein expression reporters in any way. Li's approach is essentially a nucleic-acid diagnostic tool, not a protein-expression reporter. The alleged combination of Nivala and Li thus does not cure the deficiencies noted above with respect to Nivala.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Nivala acknowledges that nanopore sensing has been used as a diagnostic tool for “biopolymers”, which includes both “nucleic acids” and “proteins” (see Nivala at pg. 1, paras. [0008]-[0011]; pg. 5, para. [0061]; and pg. 7, para. [0086]), and Nivala also teaches that the methods and devices of the disclosure may be used to detect and quantify altered protein expression (see pg. 8, para. [0092]). For at least these reasons, the references used in the prior art combination are in the same field of endeavor and are reasonably pertinent to the particular problem with which the inventor was concerned, and can be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). Furthermore, a person of ordinary skill in the art would have been able to recognize the relevant similarities and differences in detecting nucleic acids versus polypeptides when using nanopore sensing.
Le is cited by the Office Action at page 16 to describe "that fusion with Osm Y results in high levels of expression using other proteins." However, the alleged combination of Nivala, Li, and Le does not cure the deficiencies noted above with respect to Nivala and Li.
Applicant’s arguments have been fully considered but they are not persuasive.
Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references. In the instant case, Applicant’s argument does not specifically point out the deficiencies of Le.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DENNIS ARMATO whose telephone number is (703)756-5348. The examiner can normally be reached Mon-Fri 11:00am-7:30pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melenie Gordon can be reached at (571) 272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651