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 .
Applicant’s Amendment/Request for Reconsideration-After Non-Final Rejection, filed 3/05/2026, is considered and entered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Priority of US application 62/979,507 filed 02/21/2020 is acknowledged.
Claim Status
Claims 1-20 are pending and are examined on the merits.
Withdrawn Rejections/Objections
The rejections to claims 1-20 under 35 U.S.C. 102(a)(1) in the Office action mailed 06 November 2025 are withdrawn in view of claim amendments filed 3/05/2026.
Claim Rejections - 35 USC § 101
This rejection is maintained from the previous Office action. Modification is necessitated by claim amendments.
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Step 1: Process, Machine, Manufacture or Composition
Claims 1-7 are drawn to a process, here “a computer-implemented method.”
Claims 8-14 are drawn to a machine or manufacturer, here a “system.”
Claims 15-20 are drawn to a machine or manufacturer, here a “computer-program product tangibly embodied in a non-transitory machine-readable storage medium.”
Step 2A Prong One: Identification of an Abstract Idea
The claim(s) recite(s):
Generating a representation of a polymer having one or more side chains.
“Generating a representation of a polymer” is interpreted as generating a set of coordinates, which can be achieved in human mind, with or without the help of a pen and paper. Hence this step equates to an abstract idea of mental process.
Performing a molecular-dynamics simulation using the representation.
According to Specification at [005], “A representation of a polymer having one or more amino acids can be generated. A molecular-dynamics simulation can be performed using the representation. A result of the performance of the molecular-dynamics simulation includes a set of polymer conformations as a function of time.” Therefore “Performing a molecular-dynamics simulation” is interpreted as running a function of time (which can be represented by the mathematical formula f(t)). Hence this step equates to an abstract idea of mathematical concepts.
Determining, for each polymer conformation of the set of polymer conformations, one or more spatial characteristics of the polymer while in the polymer conformation.
According to the disclosure at [0005], the “spatial characteristics includes: a distance between two atoms (e.g., each of the two atoms being in a side chain of the one or more polymers or a polymer backbone chain of the polymer), an angle between three atoms in the polymer, or a dihedral angle of four atoms in the polymer backbone and the side-chain of the polymer.” Determining these parameter in the Molecular-Dynamics software will require mathematical calculations according to algorithms. Hence this step equates to an abstract idea of mathematical concepts.
Identifying, based on the one or more spatial characteristics, an incomplete subset of the set of polymer conformations estimated to undergo one or more reactions of a particular type.
This step recites a judging/decision-making activity of identifying a subset of polymer conformation that estimated to undergo reactions. This process can be achieved in human mind with the help of a pen and paper. Hence this step equates to an abstract idea of mental process.
Wherein the identifying comprises determining a water-blocking metric for a polymer conformation using a solvent-inclusive molecular dynamics simulation by tracking a quantity of one or more water molecules, and wherein the polymer conformation in the incomplete subset has a water-blocking metric within a pre-defined open or closed range of values.
The recitation “determining a water-blocking metric … using a solvent-inclusive molecular dynamics simulation by tracking a quantity of …” evaluates how effectively a material or molecular system resists or restricts the permeation of water. This would be accomplished using a mathematical function like a force field, or a distance at which the water would not come any closer to the protein. Therefore this step recites an abstract idea of mathematical concepts.
Estimating, based on a size of the incomplete subset, a probability of a reaction in which the polymer is a reactant and a particular other molecule is a product.
This step recites a judging activity (estimating) that can be achieved in human mind. Hence this step equates to an abstract idea of mental process.
Step 2A Prong Two: Consideration of Practical Application
The claims result in a process of outputting the reaction probability. The claims do not recite any additional elements that integrate the abstract idea/judicial exception into a practical application.
This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
an additional element effects a transformation or reduction of a particular article to a different state or thing; and
an additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than
a drafting effort designed to monopolize the exception.
Step 2B: Consideration of Additional Elements and Significantly More
The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea. The recited additional elements are drawn to:
Outputting the reaction probability (claims 1, 8 and 15).
One or more data processors (claim 8).
A non-transitory computer readable storage medium (claims 8 and 15).
a non-transitory machine-readable storage medium (claim 15).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because outputting data analytical results is an insignificant extra-solution activity (MPEP §2106.06(g)).
The claims do not include additional elements that are sufficient to amount of significantly more than the judicial exception because it is routine and conventional to perform the acts of data analysis/simulation/prediction in a generic computer and output the results. Other elements of the method include computer parts which are recitations of generic computer structure that serves to perform generic computer functions that are well-understood, routine, and conventional activities previously known to the pertinent industry. Viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Response to Applicant’s Argument
In the Remarks filed 3/5/2026, Applicant argues (page 10, 3rd para) that “claim 1 does not recite any judicial exceptions under Step 2A Prong One of the Alice test. Specifically, no elements in Claim 1 recite abstract ideas such as mathematical concepts or mental steps”.
In response, Applicant’s argument is not persuasive. As discussed above, claim 1 does recite abstract ideas of the mental process grouping and the mathematical concept grouping. For example, the newly amended elements:
“Identifying, based on the one or more spatial characteristics, an incomplete subset of the set of polymer conformations estimated to undergo one or more reactions of a particular type”, recites a judging/decision-making activity of identifying a subset of polymer conformation that estimated to undergo reactions. This process can be achieved in human mind with the help of a pen and paper. Hence this step equates to an abstract idea of mental process.
In the next element “wherein the identifying comprises determining a water-blocking metric for a polymer conformation using a solvent-inclusive molecular dynamics simulation by tracking a quantity of one or more water molecules, and wherein the polymer conformation in the incomplete subset has a water-blocking metric within a pre-defined open or closed range of values,” the recitation “determining a water-blocking metric … using a solvent-inclusive molecular dynamics simulation by tracking a quantity of …” evaluates how effectively a material or molecular system resists or restricts the permeation of water. This would be accomplished using a mathematical function like a force field, or a distance at which the water would not come any closer to the protein. Therefore this step recites an abstract idea of mathematical concepts.
In the Remarks, Applicant argues (page 10, 3rd para) that “examiners should consider whether the claim recites a mathematical concept or merely limitations that are based on or involve a mathematical concept. A claim does not recite a mathematical concept (i.e., the claim limitations do not fall within the mathematical concept grouping), if it is only based on or involves a mathematical concept.” Applicant has made an assertion that it is “based on math” but have not argued any additional features that is more than mere math and that must necessarily be included to achieve the claimed steps.
In response, Applicant’s argument is not persuasive. The claim 1 element, such as “wherein the identifying comprises determining a water-blocking metric for a polymer conformation using a solvent-inclusive molecular dynamics simulation by tracking a quantity of one or more water molecules, and wherein the polymer conformation in the incomplete subset has a water-blocking metric within a pre-defined open or closed range of values,” does not merely “based on”, or “involves a mathematical concept”. The recitation “determining a water-blocking metric … using a solvent-inclusive molecular dynamics simulation by tracking a quantity of …” is interpreted as a mathematical operation with input, output and algorithms. Although not expressed explicitly as a mathematical equation, it recites a mathematical operation that equivalent to a formula. Therefore this step recites an abstract idea of mathematical concepts.
In the Remarks, Applicant argues (page 11, 3rd para through page 12, 4th para) that “First, unlike the claims in Benson, Flook, Diehr or Bilski, the present performing and determining step do not recite any specific equation, formula, or concept. Second, the claimed molecular dynamics simulation in the performing step is a specific, technical, and computationally intensive process that involves simulating the physical motion of atoms over time using defined force fields and is not reducible to a mere mathematical formula or calculation. Similarly, the determining step requires determining "spatial characteristics" that explicitly comprises concrete, physical parameters”.
In response, Applicant’s argument is not persuasive.
First for the mentioned “defined force fields”, a force field is a mathematical equation. Second, ss discussed in the previous paragraph, although claim 1 does not express explicitly a mathematical equation, the recitation “determining a water-blocking metric … using a solvent-inclusive molecular dynamics simulation by tracking a quantity of …” recites a mathematical operation that is equivalent to a formula. As to the MD simulation, it is equivalent to algorithms that sustain the “physical motion of atoms over time using defined force fields”. In summary, the claims recite processes that equate to mathematics.
In re Grams, 888 F.2d 835, 837 and n.1, 12 USPQ2d 1824, 1826 and n.1 (Fed. Cir. 1989) “It is of no moment that the algorithm is not expressed in terms of a mathematical formula. Words used in a claim operating on data to solve a problem can serve the same purpose as a formula.”
Hence, "performing a molecular-dynamics simulation' is interpreted as running a function of time (which can be represented by the mathematical formula f(t))" (page 12, 3rd para) is reasonable.
In the Remarks, Applicant argues (page 13, penultimate para through page 14, 1st para) that “claim 1 cannot practically be performed in the human mind.”
In response, Applicant’s argument is not persuasive. Examiner uses broadest reasonable interpretation (BRI) when interpreting claims. The specification is not read into the claims. For example, "generating a representation of a polymer having one or more side chains" is a broad claim element. The “polymer” is given its broadest interpretation. It can be nucleic acids, polysaccharides, or proteins, or long-chain chemicals. In a simple embodiment, "generating a representation of a polymer having one or more side chains" is interpreted as generating a chemical structure of 3-5 carbons in the format of a set of coordinates (often viewed as balls and sticks, with one side chains). This step is something achievable in the human mind. A human can easily draw a set of coordinates on a paper with a pen. Therefore, claims do recite elements that can be achieved in the human mind.
In the Remarks, Applicant argues (page 14, paras 2-4) that the claim recitation “determining a water-blocking metric for a polymer conformation using a solvent-inclusive molecular dynamics simulation by tracking a quantity of one or more water molecules” does not recite a “judging/decision-making activity". Applicant then argues Examiner’s position on “estimating”.
In response, Applicant’s argument is not persuasive. “Determining” and “estimating” here are classified into judging/decision-making activities.
In molecular dynamics (MD) simulations, “tracking a water molecule” means following the complete trajectory of a specific water molecule (or set of water molecules) through the simulation time. This involves recording its positions, velocities, and sometimes orientations at each time step, so you can analyze its motion, interactions, and environment over time; a “water blocking metric” is a quantitative measure used to assess how effectively water molecules in the simulation environment are preventing the free movement of ions or other solutes through the system. Hence, the molecular dynamics (MD) simulations require mental processes (data analysis) and mathematical concepts (quantitative measure).
In the Remarks, Applicant argues (page 15, 2nd para) that “the additional elements as discussed under Step 2A Prong 1, and representative Claim 1 as a whole, integrate any alleged judicial exception into a practical application by providing a technological improvement to the field of computational modeling and molecular simulation.”
In response, Applicant’s argument is not persuasive. To integrate claims into a practical application at Step 2A/Prong one, additional elements are needed to apply, to capture and to reflect the judicial exceptions in order to integrate the judicial exceptions into a practical application. However, in the instant case, the claims result in a process of outputting the reaction probability. The claims do not recite any additional elements that integrate the abstract idea/judicial exception into a practical application.
In the Remarks, Applicant argues (page 15-16, connecting para) for a case of a technical improvement. In response, Applicant’s argument is not persuasive. What presented is actually a better data analysis, or better simulation. However they are not captured and reflected in any additional elements.
Applicant’s comparison to McRO (page 16, last two paras) is not appropriate. In McRO there is an additional element (lip synchronization) that applies, captures and reflects the judicial exceptions. Hence in McRO claims are integrated into a practical application. However for the instant case, such additional elements are not available.
Applicant’s comparison to Example 25 and 38 (page 17-20, the form) is not appropriate. In Example 38, audio signals are processed, which has nothing to do with the human mental activity. The claim is 101 eligible at Step 2A/Prong one; in Example 25, Mathematical concept is recited at Step 2A/Prong one, but an additional element (rubber curing) integrates the judicial exception into a practical application at Step 2A/Prong two. But for the instant case, such additional elements are not available.
Therefore, the 35 USC 101 rejection is maintained.
Claim Rejections - 35 USC § 103
This rejection is newly installed. Necessitated by claim amendments.
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. ("Structure based prediction of asparagine deamidation propensity in monoclonal antibodies." MAbs. Vol. 10. No. 6. Taylor & Francis, 2018. Cited on the 8/18/2022 IDS), in view of Yang et al.: ("Analysis of factors influencing hydration site prediction based on molecular dynamics simulations." Journal of Chemical Information and Modeling 54.10 (2014): 2987-2995. Newly cited).
Claim 1 is interpreted as a computerized method for estimating peptide polymer degradation by deamidation.
Regarding claim 1, Yan provides “The molecular dynamic simulations were performed with Discovery Studio, version 4.0” (page 910, col 2, last para), which is explicit for the use of software to perform the operations and implicit for the computer-implemented method.
Yan provides comparison of for HC Asn384 (A) and HC Asn389 crystal structure models (page 906, figure 3) and the structural models for HC Asn57 (page 909, figure 7), which teach generating a representation of a polymer having one or more side chains.
Yan provides “to understand the molecular basis for the biphasic nature of HC Asn384/389 deamidation, peptide geometries for HC Asn 384 and HC Asn389 from over 20 human IgG1 Fc structures available in the RCSB Protein Database Bank (PDB) were analyzed, which revealed that both residues had a favorable and an unfavorable conformation for deamidation (Figure 3 and Supplementary Table 5). Considering the orientation of side chain and distance between C-N bond (electrophile-nucleophile distance), the conformation of HC Asn384 in PDB 1FC1 with a ψ angle of −122.7º and a Cγ-N distance of 2.8Å was more favorable for deamidation than the one in PDB 4W4O with a ψ angle of 38.0º and a Cγ-N distance of 5.0Å (Figure 3A). For a similar reason, the conformation of HC Asn389 in PDB 4W4O with a ψ angle of −18.3º and a Cγ-N distance of 3.3Å was more favorable for deamidation than the one in PDB 4BYH with a ψ angle of 9.6º and Cγ-N distance of 5.0Å (Figure 3B)” (page 903, col 2, 2nd para; page 909, Fig. 7), which teaches performing a molecular-dynamics simulation using the representation, wherein a result of the performance of the molecular-dynamics simulation includes a set of polymer conformations, each polymer conformation of the set of polymer conformations identifying, for each atom in the polymer, a position of the atom.
Yan provides (page 908, col 1, 2nd -5th paras):
“The Group I Asn residues are low risk deamidation sites under both unstressed and stressed conditions because of their relatively rigid β-sheet conformations. β-sheets are the major secondary structure component in IgG mAbs. It is stabilized by multiple hydrogen bonds between adjacent β-strands and the peptide backbone has a dihedral angle (ψ) of 135° that is far from the ideal angle (ψ) of −120° needed to form the succinimide intermediate. Both factors lead to rigid peptide geometry and inhibits deamidation reaction. Consistent with this hypothesis, there were no increases in deamidation of the β-sheets Asn residues under stressed conditions (Tables 2 and 3), further indicating that these are the least favorable deamidation sites in IgG1 mAbs.
Group II Asn residues are also considered to be low risk because the Cγ-N distances were too long to form a stable succinimide intermediate. Based on the empirical data and structure analysis presented in Tables 2 and 3, Asn residues with Cγ-N distance > 3.4 Å had a low deamidation propensity. The only exceptions were LC Asn53 and HC Asn55 from mAb5, which are located at flexible loop structures with a NS sequence motif, which could deamidate under high pH stress conditions.
Group III Asn residues have a Cγ-N distance (< 3.4 Å) short enough to form the succinimide intermediate, and thus could deamidate under high pH stress conditions. However, they do not deamidate at acidic pH due to low solvent accessibility (SASA < 10 Å).2
Group IV Asn residues have Cγ-N distance < 3.4 Å and SASA values > 10 Å. These Asn residues are considered high risk deamidation sites under both unstressed and stressed conditions due to their ideal geometry for deamidation”
and Fig. 3 and 6 (page 906, Fig. 3; page 908, Fig. 6), which teaches determining polymer conformations and spatial characteristics of the polymer, and the spatial characteristics includes:
a distance between two atoms, each of the two atoms being in a side chain of the one or more polymers or a polymer backbone chain of the polymer (figures 3, 6; page 908, col 1, second paragraph);
an angle between three atoms in the polymer (page 908, figure 6; page 908, col 1, first paragraph); or
a dihedral angle of four atoms in the polymer backbone and the side-chain of the polymer (page 908, figure 6; page 908, col 1, para 1).
Yan provides Table 2 (page 903, Table 2) and Table 3 (page 905, Table 3), which teaches identifying two subsets (Asn deamidation in the Fc region and the Fv region respectively) based on structural analysis. Table 2 and 3 also teach estimating deamination reaction likelihood to be “Low”, “Moderate” or “High” in the last two columns of both tables. Deamidation is the particular reaction type.
Yan provides (page 901, section “Abstract”) “This decision tree will allow potential Asn deamidation hot spots to be identified”, (page 906, col 2, last para) “A decision tree was created to predict the deamidation propensity of Asn residues based on the observed experimental data and available structural models” and (page 903, Fig. 1 legend) “The rate determining step for the deamidation process is the cyclization step leading to the succinimide intermediate”, which suggests a decision tree/site classification system for estimating subset of incomplete polymer conformation to undergo one or more reactions of a particular type.
Yan provides Table 3 (page 905, Table 3) and Figure 1 (page 903, Fig. 1), which estimating deamination reaction likelihood to be “Low”, “Moderate” or “High” in the last two columns of both tables for polymers mAb1, mAb2, mAb3, et. al., and the L-iso-Aspartate peptide or L-Aspartate peptide is one of the molecular product (page 903, Fig. 1).
Yan provides the result of the decision tree (page 908, Fig. 6), which teaches outputting the reaction probability (output of the result of the decision tree page 908, figure 6. The output describe “High/Low Risk of Deamidation”).
Yan does not teach a water-blocking metric explicitly.
Yang provides (page 2987, section “Abstract”) “Molecular dynamics (MD) simulation based programs such as WaterMap and WATsite have been used to probe the locations and thermodynamic properties of hydration sites at the surface or in the binding site of proteins generating important information for structure-based drug design”, which teaches MD-derived hydration-site or water-occupancy/accessibility constraint (which suggests a water-blocking metric). Because WaterMap and WATsite are about hydration site analysis and displacement (page 2988, col 1, 1st para):
“WaterMap was developed to identify hydration sites in binding pockets and to evaluate the favorability of their displacement using an empirical formula based on the computed enthalpic and entropic contributions. Our previously developed hydration site analysis program, WATsite, identifies hydration sites using a MD trajectory. The thermodynamic profile of each hydration site is then estimated by computing the enthalpy and entropy of the water molecule occupying a hydration site throughout the simulation”.
Yan teaches solvent accessibility, including surface exposure-type parameters such as SASA, which provides motivation to quantify whether water/solvent can access the reactive site. Yang further teaches MD-derived hydration-site or water-occupancy/accessibility constraint. i.e., a water-blocking metric, as an implementation of the solvent-accessibility constraint.
The above rejection applies to claims 8 and 15. As Yan indicates that he used the “Graphpad Prizm” software (page 910, col 2, para 3), the “Accelerys Software” (page 910, col 2, para 4), and the “Molecular Operating Environment software package” (page 902, col 2, Table 1), which inherently suggests the computer processes and non-transitory storage media involved.
Regarding claim 2, Yan provides “Group II Asn residues are also considered to be low risk because the Cγ-N distances were too long to form a stable succinimide intermediate. Based on the empirical data and structure analysis presented in Tables 2 and 3, Asn residues with Cγ-N distance > 3.4 Å had a low deamidation propensity. The only exceptions were LC Asn53 and HC Asn55 from mAb5, which are located at flexible loop structures with a NS sequence motif, which could deamidate under high pH stress conditions” (page 908, col 1, para 3) and
“Group III Asn residues have a Cγ-N distance (< 3.4 Å) short enough to form the succinimide intermediate, and thus could deamidate under high pH stress conditions. However, they do not deamidate at acidic pH due to low solvent accessibility (SASA < 10 Å)” (page 908, col 1, para 4), which teaches a Cγ-N distance criteria and determine whether the distance criteria is satisfied in subset II and III or not.
The art applied to claim 2 also teaches claims 9 and 16.
Regarding claim 3, Yan provides (page 908, col 1, para 4) “Group III Asn residues have a Cγ-N distance (< 3.4 Å) short enough to form the succinimide intermediate, and thus could deamidate under high pH stress conditions. However, they do not deamidate at acidic pH due to low solvent accessibility (SASA < 10 Å).2”, which teaches an acidity constraint for polymer backbone amide. This Group III group constraint is not explicit on dihedral angle. However, this Group III is also constrained by a Cγ-N distance (< 3.4 Å), and the Cγ-N distance is inherently related to dihedral angle because Yan also provides (page 901, col 2, last para line 4-13) “the distance between the nucleophilic NH group of the adjacent C-terminal residue and the Cγ center of the Asn side chain (Cγ-N distance) was considered a key factor influencing the deamidation rate (Figure 1).7 It was proposed that a Cγ-N distance of 1.89 Å was favorable for forming the succinimide intermediate, and this distance could be obtained if the dihedral psi (ψ) angle for rotation around the Cα-C bond was −120° and the chi1 (Χ1) angle for rotation around the Cα-Cβ bond was 120°”. Therefore, Yan teaches the acidity constraint is further constrained by the dihedral psi (ψ) angle for rotation around the Cα-C bond was −120° and the chi1 (Χ1) angle for rotation around the Cα-Cβ bond was 120.
Hence Yan teaches the constraint criteria is satisfied for each polymer conformation in Group III.
The art applied to claim 3 also teaches claims 10 and 17.
Regarding claim 4, Yan provides (page 908, col 1, para 2-5):
“The Group I Asn residues are low risk deamidation sites under both unstressed and stressed conditions because of their relatively rigid β-sheet conformations. β-sheets are the major secondary structure component in IgG mAbs. It is stabilized by multiple hydrogen bonds between adjacent β-strands and the peptide backbone has a dihedral angle (ψ) of 135° that is far from the ideal angle (ψ) of −120° needed to form the succinimide intermediate. Both factors lead to rigid peptide geometry and inhibits deamidation reaction. Consistent with this hypothesis, there were no increases in deamidation of the β-sheets Asn residues under stressed conditions (Tables 2 and 3), further indicating that these are the least favorable deamidation sites in IgG1 mAbs.
Group II Asn residues are also considered to be low risk because the Cγ-N distances were too long to form a stable succinimide intermediate. Based on the empirical data and structure analysis presented in Tables 2 and 3, Asn residues with Cγ-N distance > 3.4 Å had a low deamidation propensity. The only exceptions were LC Asn53 and HC Asn55 from mAb5, which are located at flexible loop structures with a NS sequence motif, which could deamidate under high pH stress conditions.
Group III Asn residues have a Cγ-N distance (< 3.4 Å) short enough to form the succinimide intermediate, and thus could deamidate under high pH stress conditions. However, they do not deamidate at acidic pH due to low solvent accessibility
(SASA < 10 Å).2.
Group IV Asn residues have Cγ-N distance < 3.4 Å and SASA values > 10 Å. These Asn residues are considered high risk deamidation sites under both unstressed and stressed conditions due to their ideal geometry for deamidation.”
Which teaches identifying accessibility constraint for one amide group having the Cγ-N distance threshold (< 3.4 Å) for spatial accessibility to water molecules and
For each of the four amide groups, the accessibility constraint is based on geometrical characteristics of a succinimide intermediate when the L-Asparagine peptide degrades.
Regarding claim 5, Yan teaches everything disclosed in claim 4. Yan further discloses Fig. 6 (page 908, Fig. 6), which teaches:
The Molecular Dynamics simulation having the L-Asparagine peptide in solvent;
Determining the SASA, a water-blocking metric for the polymer conformation; and
Determining the SASA is above 10Å or below 10Å.
Yan does not teach a water-blocking metric explicitly.
Yang provides (page 2987, section “Abstract”) “Molecular dynamics (MD) simulation based programs such as WaterMap and WATsite have been used to probe the locations and thermodynamic properties of hydration sites at the surface or in the binding site of proteins generating important information for structure-based drug design”, which teaches MD-derived hydration-site or water-occupancy/accessibility constraint (which suggests a water-blocking metric). Because WaterMap and WATsite are about hydration site analysis and displacement (page 2988, col 1, 1st para):
“WaterMap was developed to identify hydration sites in binding pockets and to evaluate the favorability of their displacement using an empirical formula based on the computed enthalpic and entropic contributions. Our previously developed hydration site analysis program, WATsite, identifies hydration sites using a MD trajectory. The thermodynamic profile of each hydration site is then estimated by computing the enthalpy and entropy of the water molecule occupying a hydration site throughout the simulation”.
Yan teaches solvent accessibility, including surface exposure-type parameters such as SASA, which provides motivation to quantify whether water/solvent can access the reactive site. Yang further teaches MD-derived hydration-site or water-occupancy/accessibility constraint. i.e., a water-blocking metric, as an implementation of the solvent-accessibility constraint.
The art applied to claims 4-5 also teaches claims 11-12 and 18-19.
Claims 6-7 are interpreted as the purpose of the studies of the degradation sites in polypeptides. Regarding claim 6-7, Yan provides:
“Deamidation of neutrally charged asparagine (Asn) residues to negatively charged aspartate (Asp) or isoaspartate (isoAsp) residues is a common degradation pathway that occurs during the manufacturing and storage of monoclonal antibodies (mAbs). Deamidation of several Asn residues in the complementary determining regions (CDRs) of IgG mAbs have been reported to affect antigen binding.1–4 Recent studies have also shown that changes in the charge distribution on the protein surface could alter mAb pharmacokinetics (PK) by affecting FcRn-IgG dissociation.5,6 Thus, the potential risk of deamidation at each site needs to be evaluated to ensure product stability” (page 901, col 1, 1st para).
“A reliable model is needed to predict the propensity of Asn deamidation and design more robust protein therapeutics and develop a suitable control strategy to ensure product quality” (page 901, col 1, last para).
“Identification of asparagine (Asn) sites that are prone to deamidation is critical for the development of therapeutic monoclonal antibodies (mAbs)” (page 901, Section Abstract);
Therefore, in light of Yan’s teaching, an ordinary skilled person knows to taking the Monoclonal Antibody (mAb) polymer degradation into consideration when assessing mAb binding affinity to a target, and hence facilitating performance of the screening of mAb polymer;
Adding the mAb polymer to a list of potential polymer to be used as therapeutic agents;
Removing the mAbs (that are presumably prone to degrade)form the list;
Ranking the mAbs by their predicted probability of deamidation;
Combination of the above criteria in mAb screening.
The art applied to claims 6-7 also teaches claims 13-14 and 20.
It would have been prima facie obvious to a person of ordinary skill in art to modify Yan’s structure-based deamination prediction with Yang’s solvent-inclusive MD hydration-site/water-occupancy analysis. Because Yang address MD-based characterization of water/hydration sites in proteins, including water occupancy and conformation dependence.
One would reasonably expect success as this is a predictable substitution. Yan use structural parameters and solvent accessibility; Yang provide a known way to quantify hydration/water occupancy from MD trajectories. Substituting the static SASA/structural accessibility with MD-derived water occupancy would have been a predictable improvement.
Response to Applicant’s Argument
In the Remarks filed 3/5/2026, Applicant argued (page 21, paras 2-3) amended claim 1 now recites "a water-blocking metric" and Yan does not disclose or suggest the limitations.
In response, Applicant’s argument is not persuasive. as discussed above, Yan provides (page 901, section “Abstract”) “This decision tree will allow potential Asn deamidation hot spots to be identified”, (page 906, col 2, last para) “A decision tree was created to predict the deamidation propensity of Asn residues based on the observed experimental data and available structural models” and (page 903, Fig. 1 legend) “The rate determining step for the deamidation process is the cyclization step leading to the succinimide intermediate”, which suggests a decision tree/site classification system for estimating subset of incomplete polymer conformation to undergo one or more reactions of a particular type.
Yan does not teach a water-blocking metric explicitly, but Yang provides (page 2987, section “Abstract”) “Molecular dynamics (MD) simulation based programs such as WaterMap and WATsite have been used to probe the locations and thermodynamic properties of hydration sites at the surface or in the binding site of proteins generating important information for structure-based drug design”, which teaches MD-derived hydration-site or water-occupancy/accessibility constraint (which suggests a water-blocking metric). Because WaterMap and WATsite are about hydration site analysis and displacement (page 2988, col 1, 1st para):
“WaterMap was developed to identify hydration sites in binding pockets and to evaluate the favorability of their displacement using an empirical formula based on the computed enthalpic and entropic contributions. Our previously developed hydration site analysis program, WATsite, identifies hydration sites using a MD trajectory. The thermodynamic profile of each hydration site is then estimated by computing the enthalpy and entropy of the water molecule occupying a hydration site throughout the simulation”.
Yan teaches solvent accessibility, including surface exposure-type parameters such as SASA, which provides motivation to quantify whether water/solvent can access the reactive site. Yang further teaches MD-derived hydration-site or water-occupancy/accessibility constraint. i.e., a water-blocking metric, as an implementation of the solvent-accessibility constraint.
Therefore, the 102 rejection is withdrawn and a 103 rejection is installed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/058110 in view of Yan, Qingrong, et al. ("Structure based prediction of asparagine deamidation propensity in monoclonal antibodies." MAbs. Vol. 10. No. 6. Taylor & Francis, 2018. Cited on the 8/18/2022 IDS), and Yang et al.: ("Analysis of factors influencing hydration site prediction based on molecular dynamics simulations." Journal of Chemical Information and Modeling 54.10 (2014): 2987-2995. Newly cited). Both the instant claims and the references claim estimating peptide cleavage through simulations. Although the reference claims recite the “nucleophilic attack distance,” other than the Cγ-N distance and the SASA values criteria in estimating the propensity of deamidation, as discussed above in the 103 rejection.
Yan does not teach a water-blocking metric explicitly, but Yang provides (page 2987, section “Abstract”) “Molecular dynamics (MD) simulation based programs such as WaterMap and WATsite have been used to probe the locations and thermodynamic properties of hydration sites at the surface or in the binding site of proteins generating important information for structure-based drug design”, which teaches MD-derived hydration-site or water-occupancy/accessibility constraint (which suggests a water-blocking metric). Because WaterMap and WATsite are about hydration site analysis and displacement (page 2988, col 1, 1st para):
“WaterMap was developed to identify hydration sites in binding pockets and to evaluate the favorability of their displacement using an empirical formula based on the computed enthalpic and entropic contributions. Our previously developed hydration site analysis program, WATsite, identifies hydration sites using a MD trajectory. The thermodynamic profile of each hydration site is then estimated by computing the enthalpy and entropy of the water molecule occupying a hydration site throughout the simulation”.
Yan teaches solvent accessibility, including surface exposure-type parameters such as SASA, which provides motivation to quantify whether water/solvent can access the reactive site. Yang further teaches MD-derived hydration-site or water-occupancy/accessibility constraint. i.e., a water-blocking metric, as an implementation of the solvent-accessibility constraint.
It would have been prima facie obvious to a person of ordinary skill in art to modify Yan’s structure-based deamination prediction with Yang’s solvent-inclusive MD hydration-site/water-occupancy analysis. Because Yang address MD-based characterization of water/hydration sites in proteins, including water occupancy and conformation dependence.
One would reasonably expect success as this is a predictable substitution. Yan use structural parameters and solvent accessibility; Yang provide a known way to quantify hydration/water occupancy from MD trajectories. Substituting the static SASA/structural accessibility with MD-derived water occupancy would have been a predictable improvement (MPEP §2143. III.(B)).
This is a provisional nonstatutory double patenting rejection.
Response to Applicant’s Arguments
In the Remarks filed 3/5/2026, Applicant expressed (page 22, 2nd para) “because the current and reference applications are pending and the allowable claim scope
has yet to be determined, Applicant respectfully requests that the double patenting rejections be held in abeyance until such time as the presence of otherwise-allowable subject matter is indicated.” Applicant’s request and granted.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/GL/
Patent Examiner
Art Unit 1686
/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights