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 Group 1, claims 1-9, and the species of: compound of SEQ 3; Y45 in the disordered N-terminal domain of galectin-3; C202, K210 and A216 in the allosteric cavity of the C-terminal of galectin-3, in the reply filed on 1 December 2025 is acknowledged. Applicant states Claims 10, 16, 22, 27-29, 39 and 40 read upon the species. The species do not, at present, apply to elected Group I.
Claims 10, 16, 22, 27-29, and 39-43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
Claims 1-9 are examined upon their merits.
Claim Objections
Claim 2 is objected to for improper punctuation: See MPEP section 608.01(m), “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995)”. Appropriate correction is required.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. Specifically, paragraph [0041] contains an embedded executable code “(e.g., http://www.ncbi.nlm.nih.gov/BLAST/ or the like)”. See MPEP § 608.01.
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 1-9 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 is indefinite wherein it recites a subjective/relative claim limitations that are neither defined by the claim itself, nor defined within the specification as filed. The claim recites “disordered” and “ordered” domains of a protein; and “identifying a first set of structural conformations from the ensemble of conformations that satisfy the experimental structural NMR data or small angle X- ray scattering data of the protein”. These limitations are relative and/or user dependent. It is unclear what material criteria define ordered versus disordered domains, and it is unclear what criteria define those ensemble conformations that “satisfy” the data. A person having ordinary skill would not know which conformations directly infringe upon the limitations, and therefore the metes and bounds of “identifying” those that satisfy are indefinite. This affects the scope of all depending claims.
Claim 2 is similarly indefinite wherein it recites: “ identifying the first set of structural conformations from the ensemble of conformations that satisfy the experimental structural NMR data of the protein.” Again, this limitation is relative/user dependent and it is unclear what conformations “satisfy” the data since this relative term is neither defined by the claim itself nor the disclosure as filed. A person having ordinary skill would not know when a conformation infringes upon the method and therefore the metes and bounds of “identifying” those that satisfy are indefinite.
Claim 4 recites the limitation "the second amino acid" in Claim 1. There is insufficient antecedent basis for this limitation in the claim since Claim 1 recites only “a first amino acid” which is singular. Applicant may remedy this by amending the parent claim to read upon identifying at least one amino acid, rather than “identifying a first amino acid” in the singular.
Claim 5 recites, “wherein the first amino acid … comprises at least two amino acids.” There is no antecedent basis in the parent claim for more than one amino acid since Claim 1 recites “a first amino acid” in the singular. Further, the parent claim recites, ““identifying a first amino acid” and there is no method step whereby a second amino acid is identified within the first set of structural conformations. Additionally, this recitation does not further limit the scope of the parent claim, but rather broadens the scope. For all these reasons, the claim is indefinite.
Claim 7 is indefinite wherein it recites, “the enhanced sampling simulation” in the parent claim, Claim 1. There is insufficient antecedent basis for “the … simulation” because Claim 1 only recites an enhanced sampling and does not mention a simulation.
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 1-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to without significantly more. The claim(s) recite(s) identifying conformations that satisfy data. This judicial exception is not integrated into a practical application because the additional steps/elements do not meet any of the considerations MPEP 2106.05(a-c), (e) and (h). Furthermore, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they do not impose meaningful limits upon the judicial exception(s), but rather the only additional step (step (i) of claim 1) is insignificant pre-solution activities that are incidental to the primary process of determining binding between disordered and ordered domains of a protein or proteins.
The claims are directed to a method and methods are one of the statutory categories of invention (STEP 1:YES).
This claims recite: “identifying” (claims 1 and 2); “clustering” (claim 3); “identifying” (claim 4); and, a “simulation” (claim 7). These are abstract mental concepts that belong to enumerated group (c) of the Abstract Idea Groupings described in MPEP § 2106.04(a)(2): Mental processes — concepts performed in the human mind (including an observation, evaluation, judgment, opinion). Furthermore, the claims recite the natural law whereby a disordered domain of a protein binds to an ordered domain of the same protein, or an ordered domain of a different protein, thereby creating an ensemble conformation. This is merely an inherent function of protein-protein interaction. Therefore, the claims recite at least one judicial exception and further analysis need only progress for one of the judicial exceptions, which in this case will be the mental processes (STEP 2A, Prong One: YES).
According to Step 2A, Prong Two, set forth in MPEP 2106.04 II A (2), the claims are next evaluated with respect to whether the judicial exception is integrated into a practical application. These considerations are set forth in MPEP 2106.05 (a) through (c), (e), and (h). This analysis turns to the additional steps/elements recited within the claim. In independent claim 1 the only step in addition to the judicial exception(s) is: “(i) in silico, performing an enhanced sampling of a disordered domain of a protein binding to an ordered domain of the same protein or an ordered domain of a different protein thereby obtaining an ensemble of conformations, wherein each conformation in the ensemble comprises the disordered domain bound to the ordered domain”. Depending claims suggest the enhanced sampling is a “simulation” (claim 7). “Sampling” is recited at with such a high level of generality that it encompasses any means known in the art (see MPEP 2106.05(e)). Dependent claim 18 recites, “the enhanced sampling simulation comprises molecular dynamics, Monte Carlo, replica exchange molecular dynamics simulation, metadynamics simulation, temperature cool walking, or generalized simulated annealing art”, but these do not require a particular machine or apparatus, and use of conventional computer functions does not qualify as a particular machine (MPEP 2106.05(b)). There are no additional elements that reflect an improvement within the technical field (2106.05(a)); there are no additional elements that apply the judicial exception to a particular treatment or prophylaxis (2106.04(d)(2)); there are no additional elements that effect a particular transformation (2106.05(c)); and, there are no additional elements that apply the judicial exception in some other meaningful way beyond generally linking it to a field, namely, identifying an amino acid within a disordered domain of a protein that binds to an ordered domain of a protein.
Regarding claim 8 which provides the most detail about the method, the specification states: Conservative substitution tables providing functionally similar amino acids are well known in the art (paragraph [0038]). The specification refers to “techniques known to those of skill in the art” throughout (ex. paragraphs [0076], [0082], [0105], [0114], [0125]). Therefore, in in accordance with MPEP 2106.07(a)(III)(A), the examiner has cited express statements in the specification indicating that the additional elements were sufficiently well-known that the specification does not need to describe the particulars thereof. In other words, the disclosure describes no new technology, but merely refers to techniques and elements that were known in the art at the time of filing.
Lastly, in accordance with MPEP 2106.07(a)(III)(C), the examiner cites publications within the field of technical expertise, that demonstrate the well-understood, routine, conventional nature of the additional element(s). The following prior art teaches it was well established in the field of technical expertise that galectin-3 protein was a modular protein and chimera galectin interacts with both glycan and peptide motifs and these are determined by NMR studies (Ippel et al., cited on the IDS filed 5/2/2023, particularly Results and Discussion). Ippel et al. alter residues within the galectin protein to produce transient secondary helical confirmations and describe alterations in intramolecular interactions as well as ligand binding. Therefore, the additional steps/elements were well-understood, routine, conventional activities in the field prior to filing the application at hand (STEP 2B: NO).
Regarding the invention, Applicant’s own post-filing publication (Bhattacharya et al, Biophysical Journal, Vol. 121, Issue 22: P4342-4357, 15 November 2022) indicates the method of the claims approaches the general problem of studying intrinsic disordered regions (IDRs) within proteins by using accelerated molecular dynamics (AMD) simulations combined with existing NMR structural data, as taught by Ippel et al., to predict the binding interface of the C-terminal domain (CTD) with galectin-3’s IDR. The CTD binding/N-terminal interface, as observed in AMD simulations, includes a diverse ensemble of structures in which multiple amino acid motifs between residues 20 and 100 of Galectin-3 engage with the CTD. Applicant shows that simulated structures explain the NMR data from Ippel et al. and agree with the fuzzy complex model of IDR interaction. Therefore, this is evidence that the method of the instant claim merely appends the technique of accelerated molecular dynamics to study of the natural law, namely, the intrinsic intramolecular protein interactions within Galectin-3. In this way, the invention amounts to nothing more than the words “apply it” appended to the field of use.
The claimed steps/elements recited in addition to the judicial exception(s), alone or in combination, do not make an inventive contribution over the methods that were known in the art prior to filing, and they amount to nothing more than the judicial exception(s) itself.
For all of these reasons, Claims 1-9 are directed to the judicial exception without significantly more and are rejected.
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.
Claims 1-5 and 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated over Ippel et al., cited on the IDS filed 2 May 2023.
It should be noted that the N-terminal end of Galectin-3 contains an intrinsically disordered region (IDR) of around 80 amino acids.
Regarding claim 1, the Ippel prior art teaches analysis of the binding between a disordered domain of galectin-3 and an ordered domain within galectin-3, and the ordered domain of ligand proteins and the computer simulations produced from this NMR data (equivalent to “in silico” methods). The authors obtaining an ensemble of conformations that are analyzed by NMR. The authors identify the amino acids within those conformations that affect binding between the disordered domains of galectin-3 and ordered domains within itself or within ligands. Specifically, Galectin-3 has a modular design comprising an N-terminal tail {NT, residues 1-111) and a conserved carbohydrate recognition domain (CRD, residues 112-250). The authors create chimera-type galectins that interacts with both glycan and peptide motifs. The authors perform complete 13C/15N-assignment of the human protein and perform NMR--based analysis of its structure beyond the CRD. Using two synthetic NT polypeptides covering residues 1-50 and 51-107, evidence for transient secondary structure (equivalent to “identifying a first set of structural conformations from the ensemble” of the instant claim) was found with helical conformation from residues 5 to 15 as well as proline-mediated (which reads on “identifying a first amino acid within the first set of structural conformations” of the instant claim), multi-turn structural conformation from residues 18 to 32 and around PGAYP repeats. Intramolecular interactions occur between the CRD F-face, which is the 5-stranded beta-sheet behind the canonical carbohydrate-binding 6-stranded beta-sheet of the S-face) and NT. This teaches binding analysis of domains within the protein itself. The authors identify the sequence P23GAW26 ... P37GASYPGAY45 as the region that defines the primary binding epitope within the NT. Further, the authors identify the PGAX motif is crucial for self-interactions between NT/CAD. Finally, galectin-3 molecules can interact weakly with each other via the F-faces of their CRDs, and this interaction appears to be assisted by their NTs. The authors conclude: “our results add insight to defining binding sites on galectin-3 beyond the canonical contact area for beta-galactosides” [ABSTRACT].
Regarding claim 2, The Ippel prior art uses experimental structural NMR data to analyze the galectin-3 protein (abstract). The authors identify multiple structural conformations using the NMR data. While the authors do not teach “identifying … conformations that satisfy the experimental structural NMR data of the protein”, as stated above, “identifying” is a mental process judicial exception that is not patent eligible subject matter. Therefore, this limitation cannot be what distinguishes the invention from the prior art.
Regarding claim 3, Figure 2 demonstrates clustering the structural conformations by structural similarity to identify a template peptide (Fig. 2C).
Regarding claims 4 and 5, through 13C/15N-assignment over the entire protein, the Ippel prior art identifies the PGAX motif is crucial for galectin-3 self-interactions between NT/CAD. This teaches the method further comprising identifying amino acids (plural) within the first set of structural confirmations. The data demonstrate these residues are crucial for the interaction between domains of the same protein. Since it consists of four amino acids, the identified “amino acid within the first set of structural conformations comprises at least two amino acids”, as recited by Claim 5.
Regarding claim 8, the Ippel reference teaches methods comprising designing a plurality of template peptides that bind in silico to at least one amino acid in the ordered domain (see Figure 2C )based at least in part on the first set of structural conformations (see Figures 2 A andf B). The authors use NOE(SY) or nuclear Overhauser effect spectroscopy to examine resonance assignments for NT peptide 1-50 made by using standard 1H homonuclear protocols, primarily based on DlPSI and NOESY data. This teaches in silico mutating each amino acid residue of each of the plurality of template peptides thereby producing a plurality of mutant peptides and selecting a set of candidate peptides from the plurality of mutant peptides based on in silico binding, as claimed. The authors then synthesize each of the set of candidate peptides thereby producing a set of synthesized candidate peptides; and experimentally measuring the effect of each of the synthesized candidate peptides on galectin-3 intramolecular binding.
Regarding claim 9, the authors specifically look at intramolecular binding of the domains within galectin-3 (see Figure 4, which demonstrates NMR spectra for the Gal-3 CRD [carbohydrate recognition domain], which is in the ordered C-terminal domain, in the absence and presence of NT peptide, which comprises the intrinsically disordered domain). Therefore, the effect that the prior art looks at is binding, as claimed.
Therefore the invention of Claims 1-5 and 8-9 fails to distinguish over the methods disclosed in the prior art.
Claims 1 and 7-9 is are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lin et al., cited on the ISR filed 2 May 2023.
Regarding claim 1, Lin et al teach methods comprising, in silico, performing an enhanced sampling of a disordered domain of a protein binding to an ordered domain of the same protein. Specifically, Lin et al. teach, “Ten thousand randomized NTD conformers attached to the CRD were generated using flexible -MECCANO” modelling (pg. 17854, second column, Modelling). The authors use this in silico modelling to select ensembles (pg. 17854, second column, Modelling) and then identifying a set of structural conformations from the ensemble of conformations that satisfy the known experimental structural NMR data (see pg. 17853, first column, NMR experiments and Figure 7). The authors further identifying the amino acids within within the disordered domain of the protein (the N-terminal) that bind to the ordered domain the (CTD) of the same protein, Galectin-3 (see Figure 6).
Regarding claim 7, the reference teaches the enhanced sampling simulation comprising Monte Carlo of the instant claims (pg. 17853, first column, NMR experiments, wherein it states “Peak intensities were fitted to exponential decays with a Monte Carlo procedure to estimate fitting error.”
Regarding claim 8, the Lin et al. prior art teaches designing a plurality of template peptides that bind in silico to at least one amino acid in the ordered domain based at least in part on the first set of structural conformations, wherein it teaches “Ten thousand randomized [N-terminal domain] NTD conformers attached to the CRD were generated using flexible -MECCANO” modelling (pg. 17854, second column, Modelling). The prior art produces a plurality of N-terminal and CRD truncations (equivalent to a “a plurality of mutant peptides” of the instant claim; See Figure 3 for a summary of truncation mutants). The authors actually synthesizing each of the set of candidate peptides (see pgs. 17852-53 sections titled DNA constructs and Protein expression and purification) thereby producing a set of synthesized candidate peptides (see Figure 3 for these mutant peptides). The Lin prior art experimentally measuring the effect of each of these synthesized candidate peptides on intramolecular Galectin-3 binding (see Figure 3, Figure 5 – NMR paramagnetic relaxation studies, and Figure 6 – Hydrophobicity drives self-association of galectin-3).
Regarding claim 9, the authors specifically look at intramolecular binding of the domains within galectin-3 , wherein it states: “Here we used NMR spectroscopy, mutagenesis, small-angle X-ray scattering, and computational modeling to study the self-association-related multivalency of galectin-3 at the residue-specific level. We show that the disordered N-terminal domain (residues ~20-100) interacts with itself and with a part of the [carbohydrate recognition domain] CRD not involved in carbohydrate recognition (beta-strands 7-9; residues ~200-220)” [ABSTRACT]. Therefore, the effect that the prior art looks at is binding, as claimed.
Therefore, the method of the instant claims fails to distinguish over the methods disclosed in the prior art, and Claims 1 and 7-9 are rejected.
Conclusion
No claim is allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STACEY NEE MACFARLANE whose telephone number is (571)270-3057. The examiner can normally be reached M-F 7:30-5 (EST) & Sat. A.M..
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/STACEY N MACFARLANE/Examiner, Art Unit 1675