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 .
Election/Restrictions
Applicant’s election without traverse of claims 1-15 and 17-18 in the reply filed on March 16, 2026 is acknowledged.
Claim 16 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-15 and 17-18 are examined herein.
Specification
The Specification is objected to because it contains disclosures of polypeptide sequences that are not accompanied by SEQ ID NOS, specifically, MAESSDKLY ([00174], pg. 73 and Table 1 header, pg. 74). Even if those sequences are included in the sequence listing, a sequence identifier must accompany each sequence each time it appears in the specification. 37 C.F.R. 1.821 (a) and (c); M.P.E.P. 2422.01-03.
37 C.F.R. 1.831 Requirements for patent applications filed on or after July 1, 2022, having nucleotide and/or amino acid sequence disclosures.
(c) Where the description or claims of a patent application discuss a sequence that is set forth in the "Sequence Listing XML" in accordance with paragraph (a) of this section, reference must be made to the sequence by use of the sequence identifier, preceded by "SEQ ID NO:" or the like in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application. Where a sequence is presented in a drawing, reference must be made to the sequence by use of the sequence identifier (§ 1.832(a)), either in the drawing or in the Brief Description of the Drawings, where the correlation between multiple sequences in the drawing and their sequence identifiers (§ 1.832(a)) in the Brief Description is clear. MPEP 2412.04.
Claim Objections
Claims 7 and 17 are objected to because of the following informalities:
Claim 7 recites “binding of the affinity reagents to macromolecules of the array”, should be “binding of the affinity reagents to the macromolecules of the array”.
Claim 17 recites in step (d), last line “the first assay reagent in step (b);”, should be “the first assay reagent in step (b); and”.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites a method of analysis of an array of macromolecules using different assay reagents. Claim 1 does not recite or give any indication that the macromolecules attached to individual addresses of the array are different kinds of macromolecules or macromolecules of different structures. Therefore, the claim will be interpreted as reciting an array of macromolecules, wherein all macromolecules are of the same kind/structure. This interpretation is important for establishing antecedent base in claims 2-6 reciting “the macromolecules” and understanding if the macromolecules are of the same kind/structure, in particular, for claims 5-6.
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 1-15 and 17-18 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 1 recites “(c) determining a first observed reaction extent comprising the fraction of the individual addresses observed to react with a first assay reagent in step (b); and (d) determining a second observed reaction extent comprising the fraction of the individual addresses observed to react with a second assay reagent in step (b).” Steps (c) and (d) carry out competing reactions: i) reaction with the first assay reagent and ii) reaction with the second assay reagent. The observed reaction extents are expected to be different when both i) and ii) are run together from another scenario when i) and ii) are run separately. It is unclear what is the order of steps (c) and (d) because it is important for determining site accessibility in step (g).
Claims 2-6 recite “the macromolecules”. The antecedent basis for this limitation in the claims is unclear because parent claim 1 recites an/the array of macromolecules and the macromolecule. Claims 5-6 are particularly confusing because they imply that not all the macromolecules are of the same kind/structure. Please, see Claim Interpretation above for details. The specification does disclose that more than one protein species can be attached to the array. Therefore, a clearer indication is needed as to how many different macromolecules are attached to the array.
Claim 6 recites “wherein the macromolecules have the same molecular composition.” The term “molecular composition” is not clear in the context of the claim and the specification. In the art, “molecular composition” is rather general description of macromolecules. For example, penicillin composition can be described by the formular C16H18N2O5S and DNA can be described as being composed of nucleotides. The specification fails to provide a common meaning for this term and complicates the matter further by disclosing that “the chemical composition of an epitope can be expressed in terms of biosimilarity to another epitope” ([0097]). Perhaps, “the same molecular structure” could be a less ambiguous term.
Claim 17 recites in step (d) “the same molecular structure as the macromolecules at the fraction of the individual addresses observed to react with the first assay reagent in step (b).” The claim language can be interpreted as the macromolecules at another fraction of the individual addresses having a different structure, which is confusing because claim 17 does not recite macromolecules of different structures attached to the array. Also, please see claim 18 below for “the meaning of empirical outcome profile”, because “the fraction of the individual addresses observed to react with the first assay reagent” in claim 17 step (d) is related to it.
Claim 18 recites in step (a) the same array of macromolecules as in claim 1, which in turn is interpreted as the array with macromolecules of the same kind/structure. Claim 18 further recites in step (d) “identifying two subsets of the addresses having the similar candidate macromolecule, wherein the two subsets comprise different isoforms of the similar candidate macromolecule.”
First, it is unclear how many different molecules are attached to the array. Second, reaction outcomes for overlapping reactive sites are expected to be different for the same molecules because the first and the second assay reagent reaction times can be different due to statistical nature of the reactions. Therefore, it is unclear what “two subsets of the addresses” Applicant has in mind. For example, if the first and the second assay reagents are allowed to bind reversibly to the array of identical molecules then the overlapping binding sites will be labeled differently from one labelling run to another depending on which assay reagent, the first or second, binds to the macromolecule first.
In this context, the meaning of empirical outcome profile is unclear. The specification does not provide an unambiguous definition for “empirical outcome profile”. For example, the specification discloses “a collection of reaction outcomes for each of the addresses forms an empirical outcome profile” ([0007]). A collection of reaction outcomes for each of the addresses cannot be obtained in a single experiment, and as explained above, the reaction outcomes for each of the addresses can vary for overlapping reaction sites. Paragraph [0086] further complicates the issue: “A plurality of measurement outcomes for a given macromolecule, for example, a macromolecule present at a particular address or other unique identifier in an array, can be combined into an empirical outcome profile.” In this scenario a plurality of measurements will lead to an averaged reaction outcome for each address, provided that macromolecules at all addresses are identical. The specification fails to provide any example of an outcome profile.
Subject Matter Free of the Prior Art
Claims 1-15 and 17-18 are free of the prior art.
The prior art neither teaches nor suggests a method of determining accessibility of macromolecule structures comprising: contacting an array of macromolecules with a plurality of different assay reagents, wherein individual addresses of the array are each attached to a single macromolecule, the macromolecule comprising a plurality of different reactive sites, and wherein the different assay reagents are different with respect to specificity for the reactive sites; and detecting reaction of the array of macromolecules with the different assay reagents.
The closes prior art:
Arora et al. (CA 2635465) teach methods for mapping binding site volumes in macromolecules and creating an interaction map (Abstract), but fail to teach detecting reaction with two different assay reagents;
Qi et al. (Mol Cell Proteomics. 2021; 20:100059) teach antibody epitope mapping of hundred antibodies in a single run using a phage displayed peptide library with next generation
sequencing (Abstract), but fail to teach detecting reaction with two different assay reagents;
Evans et al. (WO 2013163348) teach processes for identification of binding sites on protein molecules using a combination of protein sequence data, structural information,
experimental data on binding affinity, and computational modeling in order to identify binding sites on protein molecules (Abstract), but fail to teach detecting reaction with two different assay reagents;
Huber et al. (Methods in Molecular Biology, vol 1785. Humana Press, New York, NY.) teach a method to map epitopes of monoclonal antibodies that bind to G protein-coupled receptors using an amber codon suppression strategy to genetically encode
photo-activatable cross-linkers (Abstract), but fail to teach detecting reaction with two different assay reagents.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander Volkov whose telephone number is (571) 272-1899. The examiner can normally be reached M-F 9:00AM-5:00PM (EST).
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached on (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDER ALEXANDROVIC VOLKOV/Examiner, Art Unit 1677
/REBECCA M GIERE/Primary Examiner, Art Unit 1677
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