DETAILED ACTION
Status of the Application
Claims 1-20 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Acknowledgment is made of a claim for domestic priority under 35 U.S. C. 119(e) to provisional application No. 63/377,249 filed on 09/27/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/20/2023 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The figure descriptions for figures 1-6 are objected to because of the following informalities: Figure 1's description states that it shows a diagram of a process of cleaving an immobilized polypeptide to produce an immobilized set of polypeptide fragments and binding assays carried out on the immobilized set of polypeptide fragments. However, the figure description does not explicitly describe the attachment of polypeptide to the particle which is depicted in the figure. Although the attachment is described elsewhere in the specification, its omission from the figure description reduces clarity. To improve understanding, the figure description should be amended to briefly mention the attachment of the polypeptide to the particle as illustrated. For Figures 2-6, neither the figures themselves nor the brief description of the drawings provide any definition or explanation for the elements labeled R1, R2 and R3 (thinner lines) and irregularly shaped closed figure depicted with a thicker line weight. This lack of definition makes the figures unclear and non-compliant with requirements of MPEP 608.02 and CFR 1.84. The applicant may remedy this by adding a concise legend or explanation clarifying these elements, provided that no new matter is introduced beyond the specification.
Appropriate correction is required.
Claim Objections
Claim 12, 13 & 15 are objected to due to the recitation of "wherein the immobilized polypeptide is…". To enhance clarity and avoid confusion, the term should be amended to recite "wherein the first immobilized polypeptide is…". Appropriate correction is required.
Claim 17 is objected to due to the recitation of "wherein the amino acid sequence of the immobilized polypeptide is different". To enhance clarity and avoid confusion, the term should be amended to recite "wherein the amino acid sequence of the first immobilized polypeptide is different". Appropriate correction is required.
Claim 19 is objected to due to the recitation of "(b) performing a binding assay… (d) performing a second binding assay… and (e) identifying the polypeptide from the results of the binding assay and second binding assay". There are two binding assays required. Therefore, to enhance clarity and avoid confusion, the claim should be amended to recite "(b) performing a first binding assay… (d) performing a second binding assay… and (e) identifying the polypeptide from results of the first binding assay and second binding assay". 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.
Claims 7, 13, 14, 15, 16 & 17 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.
Claim 7 is indefinite in the recitation of “the combined amino acid sequence of the set of fragments that is attached to the particle comprises at least 50% of the amino acid sequence of the polypeptide” for the following reasons. The term “at least 50% of the amino acid sequence of the polypeptide” is unclear. It is not apparent whether ‘50%’ refers (i) to the proportion of sequence positions of the polypeptide represented in the fragments, or (ii) to the total number of amino acid residues present in all fragments including repeated copies from multiple polypeptides. For examination purposes, claim 7 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 13 is indefinite in the recitation of “polypeptide is linked to the particle via amino acid types that are different from amino acid types that link…” for the following reasons. The term “amino acid types” is unclear in the absence of a statement indicating the “types” intended. Amino acids can be classified based on their size, their polarity, the nature of their side chains, the location of the core structural functional groups (alpha, beta, gamma), etc. As such, an amino acid type would vary. Therefore, same or different types depend on what type is being referred to. For examination purposes, claim 13 will be interpreted as a duplicate of claim 11. Correction is required.
Claim 14 is indefinite in the recitation of “wherein the total amino acid composition of the set of fragments differs” for the following reasons. Previous claims introduce two polypeptides on two different particles, implying two distinct fragment sets. However, the claim does not specify which set “the set of fragments” refers to, rendering the scope of claim 14 uncertain. For examination purposes, claim 14 will be interpreted as a duplicate of claim 11. Correction is required.
Claim 15 is indefinite in the recitation of “same type of amino acids as the amino acids that link…” for the following reasons. The term is unclear in the absence of a statement indicating the “type” intended. Amino acids can be classified based on their size, their polarity, the nature of their side chains, the location of the core structural functional groups (alpha, beta, gamma), etc. As such, an amino acid type would vary. Therefore, same or different types depend on what type is being referred to. For examination purposes, claim 15 will be interpreted as a duplicate of claim 11. Correction is required.
Claim 16 is indefinite in the recitation of “wherein the method further comprises (e) obtaining a second polypeptide from the biological sample and attaching the second polypeptide to a second particle…and (f) performing a binding assay comprising contacting the second polypeptide with a plurality of affinity reagents and detecting binding of the affinity reagents of the plurality of affinity reagents to the second polypeptide” for the following reasons. Claim 11, from which claim 16 depends, already requires the step recited in (e). Therefore, it is unclear as to how step (e) further limits the method. Claim 11 requires fragmenting the second polypeptide. Therefore, it is unclear as to how one could perform a binding assay that comprises contacting the second polypeptide (full length, not fragmented) with a plurality of affinity reagents when the method of claim 11 requires the second polypeptide to be fragmented. For examination purposes, it will be assumed that claim 16 is a duplicate of claim 11. Correction is required.
Claim 17 is indefinite in the recitation of “the amino acid sequence of the immobilized polypeptide is different from the amino acid sequence of the second immobilized polypeptide” for the following reasons. It is unclear if claim 17 requires fragmentation (per claim 11) or not (per claims 16/17). For examination purposes, claim 17 will be interpreted as a duplicate of claim 11. Correction is required.
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 and 6-8 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Beierle et al. (U.S. 2020/0348307 A1, published 11/05/2020; cited in the IDS #24).
Claim 1 and 7 as interpreted are directed in part to a method of immobilizing a polypeptide on a particle, fragmenting it, probing the resulting fragments with affinity reagents, and then identifying the polypeptide from the binding results.
For step (a), Beierle et al. teaches a method for analyzing a plurality of polypeptides immobilized on a plurality of substrates (see page 102, ¶ [0950], Example 65). Beierle et al. further teaches that the substrates include beads, nanoparticles, bar-coded particles or other solid supports (see page 101, ¶ [0945], Example 60, ¶ [0946], Example 61, listing suitable substrates). This corresponds to “attaching a polypeptide to a particle, thereby producing an immobilized polypeptide comprising a plurality of amino acids linked to the particle in step (a) of claim 1.
For step (b), Beierle et al. teaches fragmenting (e.g., a protease digestion) the polypeptide(s) immobilized on each substrate, thereby generating a set of polypeptide fragments immobilized to the substrate (see page 102, ¶ [0950], Example 65). This corresponds to ‘fragmenting the immobilized polypeptide, whereby the particle is attached to a set of fragments of the polypeptide’ in step (b) of claim 1.
For step (c), Beierle et al. teaches contacting the immobilized set of polypeptide fragments with a library of binding agents, wherein each binding agent comprises a binding moiety and a coding tag comprising identifying information regarding the binding moiety (see page 102, ¶ [0950], Example 65). This corresponds to ‘performing a binding assay comprising contacting the set of fragments with a plurality of affinity reagents and detecting binding of affinity reagents of the plurality of affinity reagents to the set of fragments’ in step (c) of claim 1.
For step (d), Beierle et al. teaches the method used in Example 65 (see page 102, ¶ [0950]) which is for determining the sequence(s) of the polypeptide or plurality if polypeptides (see page 103, ¶ [0959], Example 74). This corresponds to ‘identifying the polypeptide from results of the binding assay’ in step (d) of claim 1. Therefore, the immobilization of a polypeptide on a particle, the fragmentation, binding assay and sequencing of the polypeptide in Beierle et al. anticipate the instant claims as written/interpreted.
Claim 6 is directed to the method of claim 1, wherein the binding of the affinity reagents to the fragments is detected on the particle. For example, by detecting a signal from labels associated with affinity reagents that are bound to fragments on the particle surface.
The teachings of Beierle et al. have been discussed above with regard to claim 1. Beierle et al. further teaches the immobilized polypeptide fragments being contacted with a library of binding agents that comprise a binding moiety and a coding tag that has identifying information regarding the binding moiety (see page 102, ¶ [0950]). Therefore, the binding of binding agents to the immobilized fragments would be detected on the substrate in Beierle et al., which anticipates the instant claims as written/interpreted.
Claim 8 is directed to the method of claim 1, wherein the identifying of step (d) further comprises determining the amino acid sequence of the polypeptide.
The teachings of Beierle et al. have been discussed above with regard to claim 1. Beierle et al. further teaches determining the sequence(s) of the polypeptide or plurality of polypeptides (see examples 65 and 74 on pages 102-103, ¶ [0950], [0959]). Therefore, determining the amino acid sequence of the polypeptide that is attached to a substrate in Beierle et al. anticipates the instant claims as written/interpreted.
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.
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.
Claim(s) 2-4 are rejected under 35 U.S.C. 103 as being unpatentable over Beierle et al. (U.S. 2020/0348307 A1, published 11/05/2020; cited in the IDS #24).
Beierle et al. teaches methods in which polypeptides are immobilized to a solid support prior to labeling of the proteins. Beierle et al. further teaches that proteins can first be derivatized with reactive groups such as click-chemistry moieties (alkyne and mTet) and immobilized to beads derivatized with azide and TCO (see page 56, ¶ [0500]).
Claims 2-4 are directed to particular implementations of claim 1 in which the polypeptide is attached to the particle though multiple interactions between the polypeptide and the particle, using distinct attachment chemistries for an initial attachment and for subsequent multivalent attachments. Claim 2 recites that the polypeptide is attached to the particle by reacting a plurality of attachment moieties on the particle with the plurality amino acids to form the plurality of amino acids linked to the particle. Claim 3 further specifies that the polypeptide is first attached to the particle via a first attachment moiety and then through a plurality of second attachment moieties. Claim 4 additionally requires that the reaction of the first moiety be orthogonal to the reaction of the plurality of second functional groups.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ multiple, distinct click-reactive attachment moieties on the particle surface and complementary reactive groups on the polypeptide so that, after the initial attachment event, additional attachment moieties could react with amino acids of the already attached polypeptide. One of skill in the art would have been motivated to attach different amino acids of the polypeptide using multiple moieties on the particle’s surface for the benefit of ensuring that many sections of the polypeptide remain attached to the particle after fragmentation. A person of ordinary skill in the art would have a reasonable expectation of success at attaching different amino acids within a polypeptide using different attachment moieties because this would provide multiple attachments between the polypeptide and the particle. Bioorthogonal click-chemistry pairs such as azide-alkyne and methyltetrazine (mTet)-TCO were well known to be highly selective and mutually orthogonal, and were routinely used in combination to achieve simultaneous, independent immobilization of biomolecules. Thus, using one click-chemistry pair to form a first attachment between the polypeptide and the particle and a second, orthogonal click-chemistry pair to form additional attachments, as recited in claims 2-4, would have been a predictable use of known, mutually orthogonal click-chemistry reactions to obtain stronger more controlled attachment, with a reasonable expectation of success. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention.
Claim(s) 5 is rejected under 35 U.S.C. 103 as being unpatentable over Beierle et al. (U.S. 2020/0348307 A1, published 11/05/2020; cited in the IDS #24).
The teachings of Beierle et al. have been discussed above with regard to claim 1. Beierle et al. further teaches that proteins can be sample barcoded (i.e., indexed) via recording tags and pooled prior to cyclic binding analysis, greatly increasing sample throughput and economizing on binding reagents (see page 6, ¶ [0076]).
Claim 5 is directed to the method of claim 1, wherein the fragments of the set of fragments are not spatially resolved by the detecting.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to detect the immobilized polypeptide fragments using pooled, barcoded cyclic binding analysis, in which binding is measured on a pooled set and fragments are distinguished by barcode rather than by spatial position, thereby rendering the fragments “not spatially resolved by the detecting’ as recited in claim 5. A person of ordinary skill in the art is motivated to use this detection method for the fragments because this increases the sample throughput and reduces cost on binding reagents as taught by Beierle et al. One of skill in the art has reasonable expectation of success at implementing this detection method because this method of detection is well known in the art as evidenced by Bejerle et al. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention.
Claim(s) 9-11 and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Beierle et al. (U.S. 2020/0348307 A1, published 11/05/2020; cited in the IDS #24).
The teachings of Beierle et al. have been discussed above with regard to claim 1. Beierle et al. further teaches the polypeptide from a biological sample can be fragmented by a specific protease (see page 54, ¶ [0481]).
Claims 9-10 are directed to the method of claim 1, where the immobilized polypeptide in step (a) is from a biological sample and is fragmented by a protease that is specific for a known cleavage site. Claims 11, and 13-17 as interpreted are directed to obtaining a second polypeptide from a biological sample and attaching it to a second particle, that is fragmented producing a second set of fragments of the second polypeptide. A binding assay is performed by binding a plurality of affinity reagents to the fragments of the second set of fragments.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to fragment immobilized polypeptides from a biological sample by using a specific protease. A person of ordinary skill in the art is motivated to obtain polypeptides from biological samples and subject to immobilization, fragmentation, and binding assay sequencing, to identify and characterize endogenous proteins and biomarkers. One of skill in the art has reasonable expectation of success at implementing this detection method on a polypeptide or multiple polypeptides from biological samples because this method of detection is well known in the art as evidenced by Beierle et al. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention.
Claim(s) 12 is rejected under 35 U.S.C. 103 as being unpatentable over Beierle et al. (U.S. 2020/0348307 A1, published 11/05/2020; cited in the IDS #24).
The teachings of Beierle et al. have been discussed above with regard to claims 1, 10 and 11. Beierle et al. further teaches selecting from proteases that achieve desired sequence specific cleavage (e.g., TEV protease) or non-specific proteases such as proteinase K, trypsin, chymotrypsin, pepsin, and many more (see page 54, ¶ [0481]).
Claim 12 is directed to fragmenting first and second immobilized polypeptides obtained from a biological sample, wherein the first polypeptide is cleaved with a first protease and the second polypeptide is cleaved with a second protease that recognizes a different cleavage site.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use different proteases with different immobilized polypeptides on separate particles. A person of ordinary skill in the art is motivated to use different proteases that cut at different recognition sites to generate distinct and complementary fragment sets and obtain additional and overlapping peptides, thereby increasing sequence coverage and improving identification of protein sequences and variants. One of skill in the art has reasonable expectation of success at implementing this fragmentation method on immobilized polypeptide or multiple polypeptides from biological samples because this method of fragmentation is well known in the art as evidenced by Beierle et al. and routine proteomics workflows. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention.
Claim(s) 18 is rejected under 35 U.S.C. 103 as being unpatentable over Beierle et al. (U.S. 2020/0348307 A1, published 11/05/2020; cited in the IDS #24) in view of Kapp et al. (U.S. 2022/0227890 A1, filed 01/21/2022; cited in the IDS #28).
The teachings of Beierle et al. have been discussed above with regard to claim 1. Beierle et al. does not teach a polypeptide attached to a structured nucleic acid particle. Kapp et al. teaches capturing polypeptides from a polypeptide sample onto different structured nucleic acid particles (see page 45, ¶ [0275]).
Claims 18 is directed to the method of claim 1, where the particle that the polypeptide is immobilized on is a structured nucleic acid particle.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use a structured nucleic acid particle to immobilize a polypeptide, fragment the polypeptide, perform a binding assay and determine the identity of the polypeptide. A person of ordinary skill in the art is motivated to use structured nucleic acid particles for immobilization of polypeptides because they are programmable, easily encoded, and well suited for sequence-based readouts. One of skill in the art has reasonable expectation of success at implementing the use of structured nucleic acid particles to immobilize polypeptides for sequence determination as it is well known in the art that nucleic acid scaffolds and barcodes can be used to uniquely encode different polypeptides as evidenced by Beierle et al and Kapp et al. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention.
Claim(s) 19 is rejected under 35 U.S.C. 103 as being unpatentable over Beierle et al. (U.S. 2020/0348307 A1, published 11/05/2020; cited in the IDS #24).
The teachings of Beierle et al. have been discussed above. Beierle et al. does not teach a pre-fragmentation binding assay and performing a secondary binding assay on immobilized fragments. Beierle et al. does teach immobilizing non-fragmented (intact) polypeptides and performing a binding assay (see page 30, ¶ [0207]).
Claims 19 is directed to the method where a pre-fragmentation binding assay is conducted, the polypeptide is then fragmented and a second binding assay is conducted on the fragments. Form the two binding assays, the polypeptide is identified.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to preform pre-fragmentation binding on intact polypeptide as a control, recognizing the known biological principle that structured polypeptides often mask cryptic epitopes from binding agents until fragmentation exposes binding sites (no intact signal vs. post-fragmentation signal patterns confirms successful exposure and enables polypeptide identification). A person of ordinary skill in the art is motivated to conduct a pre-fragmentation binding assay on the intact immobilized polypeptide first because it reveals whether the native, full-length protein binds to the affinity reagent and provides a baseline for interpreting fragment binding and epitope mapping. One of skill in the art has reasonable expectation of success at implementing this baseline step as a predictable result using routine control methodology as taught by epitope masking studies where proteolysis reveals hidden sites. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention.
Claim(s) 20 is rejected under 35 U.S.C. 103 as being unpatentable over Beierle et al. (U.S. 2020/0348307 A1, published 11/05/2020; cited in the IDS #24).
Beierle et al. teaches immobilization of a plurality of polypeptides on a plurality of substrates, that are fragmented, binding assay conducted to determine the sequences of the polypeptides (see page 102, ¶ [0950], Example 65 and page 103, ¶ [0959], Example 74).
Claims 20 is directed to the method of attaching a plurality of polypeptides to plurality of particles, fragmenting the plurality of polypeptides to obtain a plurality of immobilized fragment sets, performing a binding assay on the plurality of fragment sets with a plurality of affinity reagents, and identifying the polypeptides of the plurality of polypeptides from results of the binding assay.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply single particle/polypeptide workflow to a plurality of particles/polypeptides as routine optimization to enable parallel analysis. A person of ordinary skill in the art is motivated to use a plurality of polypeptides attached to a plurality of particles and fragmenting the polypeptides to obtain a plurality of fragment sets and conduct a binding assay to get more information per experiment, which is faster and at lower cost, than testing one polypeptide at a time. One of skill in the art has reasonable expectation of success at implementing this multiplexing method given the established predictability of bead-based multiplexing. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention.
Conclusion
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DALTON KIEFER whose telephone number is (571) 272-1235. The examiner can normally be reached M-F 7:30-5 EST.
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/D.E.K./Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
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