DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission filed on 1/23/2026 has been entered and considered. Rejections and/or objections not reiterated from the previous office action mailed 10/23/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Status of the Claims
Claims 1-19 are pending and under consideration in this action. Claim 20 was canceled in the amendment filed 1/23/2026.
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, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, lnc.(38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994) ).
The disclosure of the prior-filed application, Application No. 63/040,379, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The provisional application (63/040,579) lacks support for claims 15-16 and 18 in the specification. There is not support for the therapeutic agent being a cancer drug or cytotoxic drug, for the target protein being a tumor antigen, or for any of the ADCs listed in claim 18. Accordingly, claims 15-16 and 18 are not entitled to the benefit of the prior application. The effective priority date of claims 1-14, 17, and 19 is 06/17/2020 and the effective priority date of claims 15-16 and 18 is 06/16/2021.
Response to Arguments of Priority
Applicant argues that all of the pending claims receive the benefit of Provisional Application Ser. No. 63/040,379, filed June 17, 2020. Applicant’s arguments are not persuasive for the follow reasons:
Applicant did not provide any support showing pending claims 15, 16, and 18 have support in the provisional application. The provisional specification and/or drawings do not provide support for the terms “cancer”, “cytotoxic”, “tumor”, “tumor antigen”, or the any of the list of ADCs in claim 18, as these terms are either not present or only present in the list of provisional references. Therefore, the effective priority date of claims 1-14, 17, and 19 is 06/17/2020 and the effective priority date of claims 15-16 and 18 is 06/16/2021.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
1. Claims 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for antibody-small-molecule conjugates with streptavidin-biotin as the target protein-small molecule complex, does not reasonably provide enablement for any and all antibody-small-molecule conjugates. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable?. See also In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation (MPEP § 2164.06).
The specification fails to enable the if a person of ordinary skill in the art would be faced with an undue burden of experimentation when trying to implement the invention based on the disclosure. In re Wands (858 F.2d 731 at 737, 8 USPQ2d 1400 at 1404 (Fed. Cir. 1988)) sets forth a non-exclusive list of factors by which this burden of experimentation may be judged to be due or undue; factors that are germane to the instant case include the breadth of the claims, the state of the prior art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to use the invention based on the content of the disclosure.
Claim 1 recites the limitations “receiving three-dimensional coordinates for a crystal structure of a target in complex with a small molecule”, “docking a plurality of antibody structures onto the crystal structure…” and “producing the designed antibody-small-molecule conjugate”. The specification (Para. [0051]) discloses that the protein crystal structure can be determined using NMR and/or x-ray crystallography. The protein crystal structures may also be obtained from the Protein Data Bank. The specification (Para. [0053]) also discloses that the antibody structures can be curated PDB antibody scaffolds. The specification (Para. [0052]) also discloses that any technique suitable for protein-protein/protein-peptide docking can be used for the docking of the antibody structure to the crystal structure. The specification (Para. [0059]) recites producing one or more of the designed antibody-small-molecule conjugates, as well as determine the therapeutic effects and/or efficacies of the designed antibody-small-molecule conjugates. When read in light of the specification, the claimed determination recites receiving a crystal structure for any target, docking any antibody structure to that target protein-small molecule complex using any available docking software, and after optimization of the interactions, producing any designed antibody-small-molecule conjugate.
The disclosure only provides a single working example of the claimed determination of producing the designed antibody-small-molecule conjugate using the streptavidin/biotin system (see specification Para. [0061]-[0076]). The designed 4NBX.B-biotin103v186_Fr mutant exhibited KD to be 54±3 nM when binding to mSAS27A, indicating a ~20-fold KD improvement contributed by both improved association rate and dissociate rate (Para. [0071]). The specification (Para. [0058] and [0077]) also states that the workflow can for therapeutically relevant targets and to design any antibody-small-molecule conjugate, including, but not limited to Gemtuzumab ozogamicin, Brentuximab vedotin, etc. However, the specification provides no additional guidance on specific targets, specific antibodies, specific docking protocols, or specific production methods necessary to perform the claimed invention.
Regarding the docking of any antibody structure to any target protein using any available docking software, Agrawal et al. (Benchmarking of different molecular docking methods for protein-peptide docking. BMC Bioinformatics. 19(426): 105-124 (2019); cited in the IDS dated 9/17/2021) discloses a comparison of several docking methods for protein-peptide complexes (Abstract). Agrawal et al. further discloses that the FRODOCK software performed better with blind docking (i.e., no knowledge of the binding site), while ZDOCK performed better with re-docking (i.e., using the binding site to guide docking) (Abstract). Agrawal et al. further discloses challenges in docking protein-peptide complexes, including, but not limited to the quality of the structure (Pg. 112, Col. 2, Para. 3), the degree of rotatable bonds (Pg. 112, Col. 2, Para. 3), and the docking of peptides with defined secondary structure (it is more difficult with a defined secondary structure; Pg. 114, Col. 1, Para. 1). Therefore, as disclosed by Agrawal et al, determination of the appropriate docking protocol requires significant experimentation, especially in view of targets with unknown binding sites.
Regarding the production of any designed antibody-small-molecule conjugate, Beck et al. (Strategies and challenges for the next generation of antibody-drug conjugates. Nat. Rev. Drug Discov. 16, 315-337 (2017); previously cited in the Office Action dated 4/21/2025) discloses a review on strategies to design the next generation of antibody-drug-conjugates (Title, Abstract). Beck et al. further discloses an example research and development process for the antigen CD33, which is one target for acute myeloid leukemia (AML). The antibody–drug conjugate (ADC) research and development is an iterative process with fine-tuning of all of the pieces that must fit (antigen target and biology, antibody, linker, conjugation chemistry and cytotoxic warhead) (Pg. 319, Fig. 2). Therefore, as disclosed by Beck et al., the production of the appropriate antibody-small-molecule conjugate is an iterative process requiring significant experimentation.
Because the disclosure does not provide a description of the targets, antibodies, docking protocols, or production methods that perform the claimed invention and because docking protocols and production methods are not readily available within the prior art, a person of ordinary skill in the art who wished to practice the invention would have to perform additional experimentation to make and use the invention. Specifically, that person would have to experiment to determine an appropriate NMR or X-ray structure of any target protein (or search an appropriate structure in the PDB), an appropriate antibody structure, an appropriate docking protocol, and an appropriate production method for any antibody-small-molecule conjugate. Whether or not a target protein will crystallize, whether or not an antibody structure is high enough resolution, whether or not the docking protocol is optimal, and whether or not the production method for the designed conjugate is optimal is not something that can be predicted ahead of time, only by actually performing and testing each of the steps. The vast number of target proteins, the vast number of antibody structures, the vast number of docking protocols, the vast number of production methods, and the total absence of direction from the inventor regarding how to design and produce any antibody-small-molecule complex results in that burden of experimentation being undue. The claims therefore fail to comply with the enablement requirement of 35 U.S.C. § 112(a) for all designed antibody-small-molecule conjugates.
2. Claims 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites the limitation “producing the designed antibody-small-molecule conjugate”. The specification (Para. [0008], [0027], and [0059]) broadly recites that a method for producing one or more of the designed antibody-small-molecule conjugates is included. The disclosure (Para. [0071] and Fig. 5) also recites that the final designed antibody is produced, showing a ~20-fold KD improvement over biotin/mSAWT. However, the claim is directed towards designing any and all antibody-small-molecule conjugates. The specification does not provide any support for the production of any antibody-small-molecule conjugate, only the exemplary antibody-biotin-streptavidin complex, or a description that Applicant had possession of said methods to produce any designed antibody-small molecule conjugate, as claimed. Accordingly, the disclosure is not commensurate with the written description scope of the claim. Claims 2-19 are also rejected due to their dependency from claim 1.
Claim 18 recites the limitation “wherein the ADC is Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Polatuzumab vedotin, Enfortumab vedotin, Trastuzumab deruxtecan, Sacituzumab govitecan, Belantamab mafodotin, Moxetumomab pasudotox, or Loncastuximab tesirine”. The specification (Para. [0008] and [0058]) reiterates the claim language, with a non-limiting list of the same ADCs in the claim. The claim is dependent on the method of claim 1, which is directed towards designing any antibody-small-molecule conjugate. However, the specification does not provide any support for using the steps of the method disclosed in claim 1 to design any of the ADCs listed in claim 18. For example, for Gemtuzumab ozogamicin, the specification does not provide support for CD33-calicheamicin as the target protein-small molecule complex, for the docking of any antibodies to the CD33-calicheamicin complex, or for the subsequent optimization and production of the ADC (see Abstract of Jen et al. for structural components of Gemtuzumab Ozogamicin; FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia. Clin Cancer Res; 24(14): 3242-6). Accordingly, the disclosure is not commensurate with the written description scope of the claim.
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 1-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite both (1) mathematical concepts (mathematical relationships, formulas or equations, or mathematical calculations) and (2) mental processes, i.e., concepts performed in the human mind (including observations, evaluations, judgements or opinions) (see MPEP § 2106.04(a)).
Step 1:
In the instant application, claims 1-19 are directed towards a method, which falls into one of the categories of statutory subject matter (Step 1: YES).
Step 2A, Prong One:
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong One). The following instant independent claims recite limitations that equate to one or more categories of judicial exceptions:
Claim 1 recites a mental process (i.e., an evaluation of the binding pose) in step (c) of “identifying one or more of the plurality of antibody structures with binding poses that accommodate both the CDR binding poses and the target protein-small molecule interaction”; a mental process (i.e., an evaluation of the rotamer library to determine a conjugation plan) in step (d) of “screening a rotamer library of the conjugated small molecule onto the CDR binding poses identified in (c) to identify a conjugation plan comprising a selected conjugated site on the antibody to which the small molecule is conjugated to”; and a mental process (i.e., an evaluation of the antibody-small molecule interaction for sequence adjustment and a comparison of the binding affinities) in step (e) of “adjusting the sequences of the antibody CDR loops, the antibody framework or both in the conjugation plan identified in (d) to generate an antibody capable of forming an antibody-small-molecule conjugate with the small molecule, wherein the antibody-small-molecule conjugate has a higher binding affinity to the target protein as compared to the small molecule alone or to a reference antibody-small-molecule-conjugate”.
Claim 4 recites a mental process (i.e., a comparison of binding affinities) in “wherein the binding affinity of the antibody-small-molecule conjugate to the target protein is at least two fold higher than the binding affinity of the small molecule alone or the reference antibody-small-molecule conjugate”.
Claim 5 recites a mental process (i.e., a comparison of binding affinities) in “wherein the binding affinity of the antibody-small-molecule conjugate to the target protein is at least five fold higher than the binding affinity of the small molecule alone or the reference antibody-small-molecule conjugate”.
Claim 6 recites a mental process (i.e., an observation of an interaction) in “wherein the target protein-small molecule interaction in (c) comprises an interaction between the small molecule and a variant of the target protein”.
Claim 8 recites a mental process (i.e., an evaluation of residues the specified number away from the binding site for adjustment) in “wherein adjusting the sequence of the antibody CDR loops in (e) comprises adjusting the sequence of the antibody CDR residues one, two, three, four, five, six, seven, eight, nine, or ten residues from the binding sites of the small molecule to the protein target”.
Claim 9 recites a mental process (i.e., an evaluation of the type of antibody) in “wherein the antibody is a nanobody, a monoclonal antibody, or a combination thereof”.
Claim 10 recites a mental process (i.e., an evaluation of the antibody-small-molecule conjugate properties) in “wherein the antibody-small-molecule conjugate has improved kinetics, metabolic stability, circulation half-life, solubility, systemic toxicity, or any combination of, compared to the small molecule alone”.
Claim 11 recites a mental process (i.e., an evaluation of the binding specificity) in “wherein the antibody-small-molecule conjugate has improved binding specificity to the protein target compared to the small molecule alone”.
Claim 12 recites a mental process (i.e., an evaluation of hydrogen bond formation to determine which residues to adjust) in “further comprising adjusting the sequences of the antibody CDR loops to increase H-bond formation between the antibody and the target protein surface”.
Claim 13 recites a mental process (i.e., an evaluation of the binding surface) in “wherein the binding surface for the designed antibody-small-molecule conjugate to the target protein comprises an ultra-deep pocket, broad contacting interface, or both”.
Claim 14 recites a mental process (i.e., an evaluation of the small molecule) in “wherein the small molecule is a therapeutic agent”.
Claim 15 recites a mental process (i.e., an evaluation of the small molecule) in “wherein the therapeutic agent is a cancer drug or a cytotoxic drug”.
Claim 16 recites a mental process (i.e., an evaluation of the target protein) in “wherein the target protein is a tumor antigen”.
Claim 17 recites a mental process (i.e., an evaluation of the antibody-small-molecule conjugate) in “wherein the antibody-small-molecule conjugate is an antibody-drug conjugate (ADC)”.
Claim 18 recites a mental process (i.e., an evaluation of the antibody-small-molecule conjugate / ADC) in “wherein the ADC is Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Polatuzumab vedotin, Enfortumab vedotin, Trastuzumab deruxtecan, Sacituzumab govitecan, Belantamab mafodotin, Moxetumomab pasudotox, or Loncastuximab tesirine”.
Claim 19 recites a mental process (i.e., a comparison of the sequences) in “wherein two or more of the plurality of antibody structures have different CDR sequences”.
These recitations are similar to the concepts of collecting information, analyzing it and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or mathematical relationships.
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification, and are determined to be directed to mental processes that in the simplest embodiments are not too complex to practically perform in the human mind. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind. The instant claims must therefore be examined further to determine whether they integrate the abstract idea into a practical application (Step 2A, Prong One: YES).
Step 2A, Prong Two:
In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP § 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP § 2106.04(d)(I)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP § 2106.04(d)(III)). The following independent claims recite limitations that equate to additional elements:
Claim 1 recites step (a) “receiving three-dimensional coordinates for a crystal structure of a target protein in complex with a small molecule”; step (b) “docking a plurality of antibody structures onto the crystal structure, wherein each of the plurality of antibody structures as a different complementary determining region (CDR) conformations from each other and thereby different binding pose again the target protein surface”; and step (f) “producing the designed antibody-small-molecule conjugate”.
Regarding the above cited limitations in claim 1 of (i) receiving three-dimensional coordinates for a crystal structure of a target protein in complex with a small molecule; and (ii) docking a plurality of antibody structures onto the crystal structure, wherein each of the plurality of antibody structures as a different complementary determining region (CDR) conformations from each other and thereby different binding pose again the target protein surface. These limitations equate to insignificant, extra-solution activity of mere data gathering because these limitations gather data before the recited judicial exception of identifying an antibody structure with binding poses that accommodate the CDR binding poses and the target protein-small molecule interaction (see MPEP § 2106.04(d)).
Regarding the above cited limitations in claim 1 of (iii) producing the designed antibody-small-molecule conjugate. This limitation equates to an extra-solution “apply it” step because the limitation is used to physically produce the designed conjugate without providing any details of how the production of the conjugate is accomplished for any antibody-small-molecule conjugate (see MPEP § 2106.05(f)).
Additionally, none of the recited dependent claims recite additional elements which would integrate the judicial exception into a practical application. Specifically, claims 2-3 recite further data gathering steps for loop modeling, and claim 7 further limits the rotamer library. As such, claims 1-19 are directed to an abstract idea (Step 2A, Prong Two: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The instant independent claims recite the same additional elements described in Step 2A, Prong Two above.
Regarding the above cited limitation in claim 1 of (i) receiving three-dimensional coordinates for a crystal structure of a target protein in complex with a small molecule. This limitation equates to receiving/transmitting data over a network, which the courts have established as a WURC limitation of a generic computer in buySAFE, Inc. v. Google, Inc. (765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014)).
Regarding the above cited limitation in claim 1 of (ii) docking a plurality of antibody structures onto the crystal structure, wherein each of the plurality of antibody structures as a different complementary determining region (CDR) conformations from each other and thereby different binding pose against the target protein surface. This limitation, when viewed individually and in combination, is a WURC limitation as disclosed in the instant specification (Para. [0052]). The instant specification discloses that protein-protein docketing is a technique capable of predicting the structure of proteins, protein-protein complexes, or bound structure of proteins in complex with other biological entities (such as small molecules), given the structures of known structures. The instant specification (Para. [0052]) further discloses that non-limiting exemplary methods for protein-protein docketing include SwarmDock (a flexible docking method which uses a population-based memetic algorithm to optimize parameters characterizing the orientation, position, and conformations of protein subunits), pepATTRACT, FlexPepDock, HADDOCK, and PEP-Sitefinder. The instant specification (Para. [0052]) further discloses that any technique suitable (i.e., those already available in the prior art) for protein-protein/protein-peptide docking can be used in the methods described herein, so that one or more of the plurality of antibody structures with binding poses that accommodate both the CDR binding poses and the target protein-small molecule interaction can be identified (see MPEP § 2106.05(d)(I)).
Regarding the above cited limitation in claim 1 of (iii) producing the designed antibody-small-molecule conjugate. This limitation, when viewed individually and in combination, is a WURC limitation as taught by Beck et al. (Strategies and challenges for the next generation of antibody–drug conjugates. Nat Rev Drug Discov. 16: 315-337 (2017); previously cited in the Office action dated 4/21/2025). Beck et al. discloses a review on strategies for designing and developing the next generation of antibody drug conjugates (ADCs) (Title, Abstract). Beck et al. also discloses examples of ADCs currently on the market or in the clinical pipeline in Tables 1-3, including IgG isotypes, targets, and linker-drugs (limitation (iii)) (Pg. 321-322, Table 1; Pg. 324, Table 2; and Pg. 326-327, Table 3).
The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the instant claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-19 are not patent eligible.
Response to Arguments under 35 U.S.C. 101
Applicant’s arguments filed 1/23/2026 have been fully considered but they are not persuasive.
Applicant argues that regarding steps (c) and (d), it has been argued previously by Applicant that the subject matter recited in said steps cannot reasonably be performed in the human mind, and are thus, not abstract ideas. Specifically, Applicant cites Specification Para. [0053] and [0054], and highlights that these are computationally intensive steps that could not be reasonably performed in the human mind, even if, e.g., the plurality of antibody structures was two (Applicant’s Remarks, Pg. 5-7). Applicant’s remarks are not persuasive for the following reasons:
MPEP 2106.04(a)(2)(III)(C) recites:
Using a computer as a tool to perform a mental process. … Another example is Berkheimer v. HP, Inc., 881 F.3d 1360, 125 USPQ2d 1649 (Fed. Cir. 2018), in which the patentee claimed methods for parsing and evaluating data using a computer processing system. The Federal Circuit determined that these claims were directed to mental processes of parsing and comparing data, because the steps were recited at a high level of generality and merely used computers as a tool to perform the processes. 881 F.3d at 1366, 125 USPQ2d at 1652-53.
In the instant case, steps (c) and (d) are directed towards mental processes of evaluating binding poses and evaluating a small molecule rotamer library, respectively. These steps are recited at a high level of generality and merely use computers as a tool to perform the processes, similar to Berkheimer v. HP, Inc.
Regarding step (c), the broadest reasonable interpretation (BRI) of “identifying one or more of the plurality of antibody structures with binding poses that accommodate both the CDR binding poses and the target protein-small molecule interaction” is an evaluation of the binding pose as described in Step 2A, Prong One above, which is mental process performed using the computer as a tool for visualization of the interactions. With regards to the emphasized language in Specification Para. [0053] of “ranked based on one or more interface statistics” and “passes filters selecting poses are considered to be most likely to recapitulate the natural binding modes of the corresponding antibody structures (e.g., nanobody scaffolds)”, these ranking and filtering methods are not incorporated in step (c). However, even if they were actively recited in the claim, both steps are would still be considered mental processes (i.e., evaluating a ranking and comparing one pose to a natural binding pose). Therefore, step (c) is mental process, which uses the computer as a tool.
Regarding step (d), the BRI of “screening a rotamer library of the conjugated small molecule onto the CDR binding poses identified in (c) to identify a conjugation plan comprising a selected conjugated site on the antibody to which the small molecule is conjugated to” is an evaluation of the rotamer library to determine a conjugation plan, using the computer as a tool. With regards to the emphasized language in Specification Para. [0054]), this step is also a mental process as it is merely evaluating different side chain conformations or protonation states to determine the best conjugation plan. This step uses a computer as a tool to visualize the conformations or protonation states, but the evaluation of appropriate conjugation plan is still a step capable of being performed in the human mind, using the computer as a tool. Therefore, step (d) is also a mental process, which uses the computer as a tool. This argument is thus not persuasive.
Applicant argues that regarding step (e), Applicant respectfully submits that any comparison or evaluation recited in the claims is a characterization of a physical property of the generated antibody, and this portion of the claim is not directed to the comparison itself. When evaluating whether a claim limitation is directed to a judicial exception, the MPEP notes the importance of distinguishing whether claim limitations are directed to a judicial exception, or a claim involves a judicial exception. Applicant respectfully submits that the language related to the "higher binding affinity" as recited in claim 1 is a description of the generated antibody designed by the claimed method (Applicant’s Remarks, Pg. 7-9). Applicant’s arguments are not persuasive for the following reasons:
As discussed in Step 2A, Prong One above, the BRI of step (e) is an evaluation of the antibody-small molecule interaction for sequence adjustment and a comparison of the binding affinities. Similar to steps (c) and (d) above, step (e) uses the computer as a tool. The adjustment of the sequences of the CDR loops and/or the antibody framework based on the conjugation plan identified in (d) is a process that can be performed mentally or with the aid of a computer. The BRI of sequence adjustment is the modification of one or more residues, which a person can practically perform in the human mind, with the aid of a computer. Therefore, step (e) is directed towards a mental process. The limitation of “wherein the antibody-small-molecule conjugate has a higher binding affinity to the target protein as compared to the small molecule alone or to a reference antibody small-molecule conjugate” further limits the mental process of adjusting the sequences of the antibody. This argument is thus not persuasive.
Applicant argues that the claims integrate any alleged judicial exception into a practical application because the claims improve design of antibodies for use as antibody-small molecule conjugates, such that the produced antibody-small molecule conjugates have improved binding to targets. As an initial matter, Applicant respectfully submits as described above that step (e) does not recite a judicial exception. Indeed, this portion of the claim is an additional element that integrates any alleged judicial exception into a practical application (Applicant’s Remarks, Pg. 9-10). Applicant’s arguments are not persuasive for the following reasons:
MPEP 2106.04(d)(II) recites:
The analysis under Step 2A Prong Two is the same for all claims reciting a judicial exception, whether the exception is an abstract idea, a law of nature, or a natural phenomenon (including products of nature). Examiners evaluate integration into a practical application by: (1) identifying whether there are any additional elements recited in the claim beyond the judicial exception(s); and (2) evaluating those additional elements individually and in combination to determine whether they integrate the exception into a practical application, using one or more of the considerations introduced in subsection I supra, and discussed in more detail in MPEP §§ 2106.04(d)(1), 2106.04(d)(2), 2106.05(a) through (c) and 2106.05(e) through (h).
As described in Step 2A, Prong One and the arguments directly above, step (e) has been identified as a reciting a judicial exception. The integration of a judicial exception into a practical application can only be achieved by additional elements, not by a limitation that recites a judicial exception. Thus, the recited limitation is not considered as an improvement in the design of antibodies for use as antibody-small molecule conjugates. This argument is thus not persuasive.
Applicant argues that step (f) of producing the designed antibody-small-molecule conjugate is directed to the antibody and antibody-small conjugate generated, which is defined as having the recited property, e.g., improved binding affinity to a target protein. Applicant respectfully submits that this is similar to, e.g., "[p]articular computerized method of operating a rubber molding press, e.g., a modification of conventional rubber-molding processes to utilize a thermocouple inside the mold to constantly monitor the temperature and thus reduce under- and over-curing problems common in the art, Diamond v. Diehr, 450 U.S. 175, 187 and 191-92, 209 USPQ 1, 8 and 10 (1981)," which is included in the MPEP as an example of improvements "in existing technology." See e.g. MPEP § 2106.05(a)(II). (Applicant’s Remarks, Pg. 10-11). Applicant’s arguments are not persuasive for the following reasons:
As described in Step 2A, Prong Two above, step (f) equates to an extra-solution “apply it” step because the limitation is used to physically produce the designed conjugate without providing any details of how the production of the conjugate is accomplished for any antibody-small-molecule conjugate. This is equivalent to an attempt to cover any solution with no restriction on how the result is accomplished and no description of the mechanism for accomplishing the result (see MPEP § 2106.05(f)). Further analysis in Step 2B shows that step (f) is a WURC limitation as taught by Beck et al., disclosing the design and production of numerous antibodies currently in the clinic (see Beck et al., Tables 1-3).
Regarding Diamond v. Diehr, the additional elements as a whole provided eligibility and did not merely recite calculating a cure time using the Arrhenius equation "in a rubber molding process". Instead, the claim in Diehr recited specific limitations such as monitoring the elapsed time since the mold was closed, constantly measuring the temperature in the mold cavity, repetitively calculating a cure time by inputting the measured temperature into the Arrhenius equation, and opening the press automatically when the calculated cure time and the elapsed time are equivalent. These specific limitations act in concert to transform raw, uncured rubber into cured molded rubber (see MPEP § 2106.05(h)). In the instant case, step (f) is broadly reciting the production of any designed antibody-small-molecule conjugate, without reciting any steps on how to accomplish the production. Step (f) does not amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Therefore, step (f) does not amount to significantly more than the judicial exception itself. This argument is thus not persuasive.
Applicant argues that steps (a) and (b) were acknowledged in the Office Action as reciting additional elements. The Office Action alleges that both of the above additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Applicant first notes that step (b) was acknowledged as nonobvious, and that indeed "neither Cheng et al. nor Liu et al. teaches the docking of antibody structures with different CDR conformations onto a crystal structure of a small molecule-protein complex." Thus, Applicant respectfully submits that step (b) is not well-understood or routine and therefore the claim as a whole, amounts to significantly more than the judicial exception itself (Applicant’s Remarks, Pg. 11-12). Applicant’s arguments are not persuasive for the following reasons:
As described in Step 2A, Prong Two above, steps (a) and (b) recite additional elements that equate to insignificant, extra-solution activity of mere data gathering. Further analysis in Step 2B shows that step (a) equates to receiving data over a network, which is a WURC limitation of a generic computer. Step (b) is a WURC limitation as taught by the instant specification, disclosing that any suitable technique (i.e., those already known in the art) can be used to perform the protein-protein docking recited in step (b). Cheng et al. and Liu et al. are not relied upon for the analysis of step (b). Steps (a) and (b) are therefore well-understood, routine or conventional, and this argument is thus not persuasive.
Applicant argues that even if both steps (a) and (b) were individually well-understood or routine, the combination of the two is not (Specification, Para. [0005]). These additional elements therefore contribute to solving the problem "for designing antibody-small-molecule conjugates" as described in the specification, taking into account both the antibody and small molecule components, and streamlining design (Applicant’s Remarks, Pg. 12). Applicant’s arguments are not persuasive for the following reasons:
MPEP 2106.05(g) recites:
The term "extra-solution activity" can be understood as activities incidental to the primary process or product that are merely a nominal or tangential addition to the claim. Extra-solution activity includes both pre-solution and post-solution activity. An example of pre-solution activity is a step of gathering data for use in a claimed process, e.g., a step of obtaining information about credit card transactions, which is recited as part of a claimed process of analyzing and manipulating the gathered information by a series of steps in order to detect whether the transactions were fraudulent.
As described in Step 2B above, steps (a) and (b) are WURC limitations of a generic computer (receiving crystal data) or as taught by the instant specification (docking). When considered in combination, steps (a) and (b) are both data collecting steps used in the subsequent steps to optimize the interactions for a given antibody-protein-small molecule complex. This is similar to the example recited in MPEP 2106.05(g) above, wherein the recited pre-solution activity is merely gathering credit card data for the subsequent analysis for fraudulent transactions. Therefore, when considered in combination, steps (a) and (b) do not amount to significantly more than the judicial exceptions. This argument is thus not persuasive.
Applicant argues that this example is similar to Example 31 of the USPTO Subject Matter Eligibility Examples. The independent claim in Example 31 recites a method for screening for BRCA1 gene mutations. Dependent claim 70 further recites "wherein said comparing BRCA1 sequences further comprises: hybridizing a wild-type probe to a BRCA1 gene isolated from said sample; and detecting the presence of a hybridization product by measuring conformational changes in the probe that are indicative of hybridization to the BRCA1 gene with scanning near-field optical microscopy." In this example, although the independent claim was found to be patent ineligible, dependent claim 70 reciting additional elements was found patentable for amounting to significantly more than the exception itself. Similarly, even if step (b) were well understood and or routine, which Applicant does not concede, where the crystal structures "of a target protein in complex with a small molecule" as retrieved in step (a) are then used as recited in step (b), is not. Applicant submits that these additional elements meaningfully limit the claim and thus the claim as a whole is not directed to a judicial exception (Applicant’s Remarks, Pg. 13). Applicant’s arguments are not persuasive for the following reasons:
As described in the arguments directly above, the combination of steps (a) and (b) are merely gathering data for use in subsequent optimization steps. Therefore, steps (a) and (b) do not meaningfully limit the claim and do not amount to significantly more than the judicial exceptions. This argument is thus not persuasive.
Conclusion
No claims allowed.
Claims 1-19 appear to be free from the prior art because the prior art does not fairly suggest or teach the docking of antibody structures with different CDR conformations onto a crystal structure of a small molecule-protein complex, as disclosed in the conclusion of the Office action mailed 10/23/2025.
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/D.P.S./Examiner, Art Unit 1687
/Lori A. Clow/Primary Examiner, Art Unit 1687