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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/30/2025 has been entered.
Information Disclosure Statement
The Information Disclosure Statement filed 12/30/2025 is acknowledged and has been considered.
Drawings
The Drawings filed 08/11/2022 and 10/17/2022 are accepted by the Examiner.
Priority
This Application claims benefit of priority to Provisional Application (PRO) 63/221,436 filed 07/12/2021 and is a Continuation in Part (CIP) of Application 17/863,303 filed 07/12/2022. However, support for the instant claims is not found in the PRO or CIP. As such, the effective filing date of the claimed invention is 08/11/2022.
Amendment and Claim Status
In the reply filed on 12/30/2025, Applicant amended claims 1, 21-24 and 35-36 and added new claim 37. Claims 25-34 remain withdrawn for not being encompassed by the elected group.
Claims 1-37 are currently pending.
Claims 25-34 are withdrawn.
Claims 1-24 and 35-37 are under examination.
Claim Objections
Claims 35-37 are objected to because of the following informalities: Claims 35-36 are missing a comma after “the method of claim 21”. Additionally, claims 35-37 have ‘Claim’ capitalized in the phrase, “The method of Claim …”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 37 is 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. This is a new matter rejection.
Claim 37 recites “further comprising (i) adjusting a process parameter in which the at least one PTM is present if required based on the effect of the at least one PTM determined in step (h)” in lines 1-3. Applicant indicated support for this limitation could be found in Paragraphs [0004]-[0007] of the Specification. Paragraphs [0004]-[0007] generally discuss what a critical quality attribute (CQA) is, how CQAs can be identified and an overview of a method for determining if an attribute has an effect on binding of the protein of interest to a capture molecule. Paragraphs [0004]-[0007] do not provide support for “further comprising (i) adjusting a process parameter in which the at least one PTM is present if required based on the effect of the at least one PTM determined in step (h),” as recited in newly added claim 37. This is new matter.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 16-19 and 37 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 16 recites the limitation "further comprising subjecting said flow-through to enzymatic digestion after step (b) and before step (c)" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 1, the claim from which claim 16 depends, as-amended does not recite a flow-through until step (d). Thus, claim 16 lacks antecedent basis. For the purposes of compact prosecution, the claim is being interpreted as subjecting the flow-through to enzymatic digestion after step (d) and before step (e). Claims 17-19 depend on claim 16 and lack antecedent basis for the same reason.
Claim 37 recites “further comprising (i) adjusting a process parameter in which the at least one PTM is present if required based on the effect of the at least one PTM determined in step (h)” in lines 1-3. It is unclear exactly what this claim is intending to limit. First, it appears the claim is missing a comma before and after ‘if required,’ making it hard to properly interpret the claim. Second, it is unclear if one of the steps (a-h) in the method recited in claim 1 is what would be adjusted or if there are other unrecited steps that would be adjusted. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention because the metes and bounds of “further comprising (i) adjusting a process parameter in which the at least one PTM is present if required based on the effect of the at least one PTM determined in step (h)” are unclear. Additionally, it is unclear if this limitation is actually a required limitation, or simply an option because the claim states “adjusting a process parameter … if required …”. Thus, claim 37 is indefinite.
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 1-24 and 35-37 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite “determining” an effect of at least one post-translational modification (PTM) on binding of a protein of interest to a capture molecule, (g) “comparing” said amount to an amount quantitated in a control sample and (h) “using said comparison to determine” an effect of said at least one PTM on binding of said protein of interest to said capture molecule.
The limitations of determining an effect of at least one post-translational modification (PTM) on binding of a protein of interest to a capture molecule by comparing values, as drafted, is a process that, under its broadest reasonable interpretation, covers a mental process. That is, nothing in the claim precludes the step from practically being performed in the mind. For example, “determining” in the context of this claim encompasses the user manually calculating an effect of at least one PTM on binding of a protein of interest to a capture molecule. Similarly, the limitation of (g), comparing said amount to an amount quantitated in a control sample, as drafted, is a process that, under its broadest reasonable interpretation, covers a mental process. For example, “comparing” in the context of this claim encompasses the user thinking about the amount of variant in the flow-through and the amount of variant in the control sample and making a mental determination about the correlation. If a claim limitation, under its broadest reasonable interpretation, covers performance of the limitation in the mind, then it falls within the “Mental Processes” grouping of abstract ideas. As such, the claims recite an abstract idea.
This judicial exception is not integrated into a practical application. In particular, the claims only recite steps regarding data gathering to perform the determining and comparing steps. The data gathering in all steps of the method are recited at a high-level of generality such that it amounts to no more than mere instructions to apply the exception. Accordingly, these additional steps do not integrate the abstract idea into a practical application because they do not impose any meaningful limits on practicing the abstract idea. Therefore, the claims are directed to an abstract idea.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As discussed above with respect to integration of the abstract idea into a practical application, the additional elements of data gathering steps amount to no more than mere instructions to apply the exception. Mere instructions to apply an exception using data gathering steps cannot provide an inventive concept. Additionally, the steps of providing a sample, contacting the sample to a capture molecule, collecting a flow-through, contacting the flow-through to a separation column and analyzing the resultant data are all well-understood, routine and conventional steps, as discussed in the prior art. Thus, the claims are not patent eligible.
For the forgoing reasons, the invention as claimed is not deemed to encompass patent eligible subject matter under 35 U.S.C. 101.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 1-6, 9-10, 14-24 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Bondarenko et al. (WO 2020/247790 A1, 10/12/2020) (IDS Reference).
Regarding claim 1(a)-(c), Bondarenko et al. disclose methods for identifying attributes of a therapeutic protein that affect an interaction between the therapeutic protein and a target, wherein a bead bound to a capture molecule or a cell expressing on its surface a capture molecule is used (See entire document, Paragraph [0015]). Stressed therapeutic proteins are contacted with the beads or cells (Paragraph [0015]). The capture molecule is the target (Paragraph [0015]). Attributes include post-translational modifications of therapeutic proteins (Paragraph [0146]). Bondarenko et al. disclose a specific embodiment, Example 7, demonstrating a competitive size exclusion chromatography (SEC) affinity separation for identification of antibody modifications impacting binding to target protein (Paragraph [00144]).
A large number of attributes are typically identified for therapeutic proteins including glycosylation, hydroxylation, glycation, deamination, oxidation, isomerization clips and other chemical modifications. Attributes include post-translation modifications of therapeutic proteins taking place during cell culture and chemical modifications/degradations occurring during production, purification, formulation and storage. Some of these modifications occur in binding regions and may impact binding to target and efficacy. Efficacy of therapeutic protein is one of the main criteria for attribute criticality assessment. The method describes the experimental criticality assessment of attributes by competitive affinity binding between an antibody and its target Her2, followed by size exclusion chromatography (SEC) fractionation and LC-MS/MS peptide mapping characterization of bound and unbound therapeutic proteins (Paragraph [00146]).
In this method, the characterization includes identification and quantitation of modifications in the bound and unbound therapeutic faction with the goal to identify the critical quality attributes responsible for the loss of binding (Paragraph [00150]). The method was applied to several antibody:target complexes by mixing them in a ratio defined by stoichiometry of interactions, typically 1:2 (Paragraph [00150]). When a smaller amount of the receptor was provided (1:1), the antibody species with modifications reducing binding would elute as unbound from SEC (Paragraph [00150]). The disclosure of Bondarenko et al. of using the smaller amount of receptor, 1:1, leading to reduced binding among antibody species with modifications so the unbound would elute, reads on determining an amount of capture molecule immobilized on a solid surface to contact with the sample wherein the solid surface binds a determined percentage and the percentage is less than 100%.
Regarding claim 1(d) and (e), Bondarenko et al. disclose the beads bound to the target are loaded onto a column (Paragraph [0015]). The stressed therapeutic proteins are loaded onto the column and the flow through contains the unbound fraction (Paragraph [0015]). The bound fraction is separately eluted and collected (Paragraph [0015]). Additionally, the mixture is separated into at least two fractions using a technique that separates components of a mixture based on size, optionally, wherein the technique is size exclusion chromatography (Paragraph [0063]).
Regarding claim 1(f), Bondarenko et al. disclose for each of the unbound fraction and bound fraction, quantifying the abundance of the known structure (e.g., attribute) (Paragraph [0033]).
Regarding claim 1(g), Bondarenko et al. differ from instant claim 1(g) insofar as not explicitly disclosing comparing said amount to an amount quantitated in a control sample. However, Bondarenko et al. do disclose the stress causes a reduced level of interactions between the therapeutic protein and its target. In some aspects, the stress causes an about 10% to about 50% reduction in interactions, relative to interactions in corresponding conditions lacking the stress (Paragraph [0055]). Considering a control sample is simply a sample that does not receive the experimental treatment, Bondarenko et al.’s disclosure of corresponding conditions lacking the stress reads on a control sample.
Regarding claim 1(h), Bondarenko et al. disclose when the abundance of a structure, e.g., attribute, in the unbound fraction is greater than the abundance of the structure, e.g., attribute, in the bound fraction, the structure, e.g., attribute, negatively affects the interaction between the therapeutic protein and the target (Paragraph [0005]).
Bondarenko et al. do not disclose all of the above recited steps in one single embodiment.
However, Bondarenko et al. specifically disclose multiple methods of identifying structures, e.g., attributes, of a therapeutic protein or target that effect an interaction between the therapeutic protein and the target which comprises applying a stress to a sample comprising therapeutic proteins, contacting the stressed sample with target to form a mixture, separating the mixture into bound and unbound and then analyzing the bound and unbound (Abstract). Thus, it would have been obvious to one of ordinary skill in the art to follow said steps and utilize any or all of the disclosed separation and analysis techniques to effectively identify attributes of the therapeutic protein that affect binding between the therapeutic protein and the target.
Regarding claims 2 and 3, Bondarenko et al. disclose wherein the therapeutic protein comprises an antibody (Claim 54).
Regarding claim 4, Bondarenko et al. disclose wherein the antibody can be monoclonal antibody (Paragraph [0081]).
Regarding claim 5, Bondarenko et al. disclose the target can comprise an antigen for the antibody (Paragraph [0032]).
Regarding claim 6, Bondarenko et al. disclose a capture molecule bound to a solid support, optionally, a bead (Paragraph [0006]).
Regarding claim 9, Bondarenko et al. disclose (i) adding the mixture to a container comprising beads bound to the capture molecule or cells expressing at its surface the capture molecule, (ii) centrifuging the container to obtain a supernatant and a pellet, (iii) collecting the supernatant from the pellet to obtain the unbound fraction (Claim 29 of Bondarenko et al.).
Regarding claim 10, Bondarenko et al. disclose the mixture is separated into at least two fractions using a technique that separates components of a mixture based on size, charge, hydrophobicity, affinity for a capture molecule, or a combination thereof (Claim 25 of Bondarenko et al.). The method of claim 25, wherein the technique is size exclusion chromatography (SEC), affinity chromatography, precipitation using beads or cells, free flow fractionation (FFF), ion exchange chromatography (IEX), hydrophobic interaction chromatography (HIC), or ultracentrifugation (UC) (Claim 26 of Bondarenko et al.).
Regarding claims 14, 18 and 19, Bondarenko et al. disclose LC-MS/MS peptide mapping analysis of the digested Antibody 1 samples were performed on an Agilent 1290 UHPLC system connected to a Thermo Scientific Q-Exactive Biopharma mass spectrometer (Paragraph [00112]).
Regarding claim 15, Bondarenko et al. disclose affinity separation (affinity enrichment) of strongly-bound therapeutic protein-target complexes and unbound modified therapeutic protein is performed using binding target immobilized onto resin beads (Paragraph [00126]).
Bondarenko et al. do not explicitly state the enrichment being relative to said control sample.
However, as disclosed above regarding claim 1(g), Bondarenko et al. do disclose a control sample. As such, it would have been prima face obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the flow-through containing the bound therapeutic protein and unbound modified therapeutic protein would be enriched relative to the control sample in the method of Bondarenko et al. as the control sample would have lacked the stress that caused that caused the therapeutic proteins to become modified and would therefore not be enriched for such.
Regarding claims 16 and 17, Bondarenko et al. disclose each of the unbound fraction and bound fraction are subjected to a peptide digestion step, optionally, a trypsin digestion step, prior to the quantifying step or identifying and quantifying step (Paragraph [0070]).
Regarding claim 20, Bondarenko et al. disclose peptide mapping of the bound and unbound antibody molecules identified and quantified 275 chemical modifications, of which 10 were located at complementary determining regions (Paragraph [00142]).
Regarding claim 37, see 112b above. As it is unclear exactly what claim 37 is intended to mean, the disclosure of Bondarenko et al. of changing the amount of receptor present so that the antibody species with modifications that reduce bonding would elute (Paragraph [00152]) reads on adjusting a process parameter based on the effect of the PTM.
Claims 7 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Bondarenko et al. (WO 2020/247790 A1, 10/12/2020) (IDS Reference) as applied to claim 1 above, and further in view of Jooss et al. (US 2022/0162320 A1, 05/26/2022).
The teachings of Bondarenko et al. are discussed above.
Regarding claim 7, Bondarenko et al. do not disclose wherein said beads are agarose or magnetic beads.
However, Jooss et al. disclose the antibody or binding partner is bound to a solid support or matrix, such as a magnetic bead, to allow for separation of cells for positive and/or negative selection (Paragraph [0803]).
Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. As such, it would have been prima facie obvious to one of ordinary skill in the art to have used magnetic beads in the method of Bondarenko et al. since the method does not require a particular type of bead and magnetic beads are known and effective beads for separation of components as taught by Jooss et al.
Regarding claim 8, Bondarenko et al. do not disclose wherein immobilizing comprises contacting a biotinylated capture molecule to an avidin- or streptavidin-bound solid surface.
However, Jooss et al. disclose the magnetically responsive particles are coated in primary antibodies or other binding partners, secondary antibodies, lectins, enzymes, or streptavidin. In certain embodiments, streptavidin-coated magnetic particles are used in conjunction with biotinylated primary or secondary antibodies (Paragraph [0808]).
Exemplary rationales that may support a conclusion of obviousness include combining prior art elements according to known methods to yield predictable results. See MPEP 2143(I)(A). As such, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized biotinylated antibodies, reading on a capture molecule, to bind, reading on immobilize, their binding partner, the streptavidin-coated magnetic particles, in the method of Bondarenko et al. as it amounts to combining prior art elements according to known methods to yield predictable results.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Bondarenko et al. (WO 2020/247790 A1, 10/12/2020) (IDS Reference) as applied to claim 1 above, and further in view of Yan et al. (Analytical Chemistry, 10/03/2018).
The teachings of Bondarenko et al. are discussed above.
Bondarenko et al. do not disclose wherein the separation column is a strong cation exchange chromatography column.
However, Yan et al. teach the use of strong cation exchange chromatography. Yan et al. disclose a method that combines a generic strong cation exchange (SCX) chromatography step with an ultrasensitive online native MS analysis (SCX-MS) optimized for mAb separation and detection (Abstract). The combination of efficient upfront chromatographic separation and highly sensitive MS analysis allows the detection or minor variants present at very low levels (Results and Discussion).
Exemplary rationales that may support a conclusion of obviousness include combining prior art elements according to known methods to yield predictable results and use of known technique to improve similar devices (methods, or products) in the same way. See MPEP 2143(I)(A)(C). As such, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used strong cation exchange chromatography with SCX-MS in the method of Bondarenko et al. motivated by the desire to detect a monoclonal antibody (mAb) that may only be present at a low abundance as taught by Yan et al. as it amounts to combining prior art elements according to know methods to yield predictable results and to use a known technique to improve the method.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Bondarenko et al. (WO 2020/247790 A1, 10/12/2020) (IDS Reference) as applied to claim 1 above, and further in view of Kremer et al. (JP 2013540787 A, 11/07/2013).
The teachings of Bondarenko et al. are discussed above.
Bondarenko et al. do not disclose wherein the separation column is an anion exchange chromatography column.
However, Kremer et al. disclose a process for the isolation and purification of proteins such as monoclonal antibodies. Kremer et al. disclose for further purification of the antibody, two options are (1) cation exchange chromatography in the mode of binding and elution followed by anion exchange in the flow through mode (Page 3, Paragraph 2).
Exemplary rationales that may support a conclusion of obviousness include combining prior art elements according to known methods to yield predictable results. See MPEP 2143(I)(A). As such, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used anion exchange chromatography in the method of Bondarenko et al. motivated by the desire to isolate and purify the monoclonal antibodies present in the flow-through as taught by Kremer et al. as it amounts to combining prior art elements according to know methods to yield predictable results.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Bondarenko et al. (WO 2020/247790 A1, 10/12/2020) (IDS Reference) as applied to claim 1 above, and further in view of Yan et al. (US 2020/0132697 A1, 04/30/2020) (IDS Reference).
The teachings of Bondarenko et al. are discussed above.
Bondarenko et al. do not disclose wherein quantitation comprises intact mass spectrometry analysis.
However, Yan et al. disclose native mass spectrometry represents a valuable technique in the analysis of intact proteins and has been integrated into many routine analytical workflows for monoclonal antibody (mAb) heterogeneity assessment (Paragraph [0117]).
Exemplary rationales that may support a conclusion of obviousness include combining prior art elements according to known methods to yield predictable results and use of known technique to improve similar devices (methods, or products) in the same way. See MPEP 2143(I)(A)(C). As such, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used intact mass spectrometry analysis in the method of Bondarenko et al. since the method does not require a particular type of mass spectrometry and intact mass spectrometry is a known and effective means of monoclonal antibody heterogeneity assessment as taught by Yan et al.
Claims 21-24 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Bondarenko et al. (WO 2020/247790 A1, 10/12/2020) (IDS Reference) in view of Shi et al. (MAbs, 01/01/2021) (IDS Reference).
The teachings of Bondarenko et al. are discussed above.
Regarding claim 21(a), Bondarenko et al. disclose a method of identifying attributes of a therapeutic protein that affect an interaction between the therapeutic protein and a target, wherein a bead bound to a capture molecule or a cell expressing on its surface a capture molecule is used. Stressed therapeutic proteins are contacted with the beads or cells. The capture molecule is the target (Paragraph [0015]). Attributes include post-translational modifications of therapeutic proteins (Paragraph [0146]).
Regarding claim 21(b) and (c), Bondarenko et al. disclose the beads bound to the target are loaded onto a column. The stressed therapeutic proteins are loaded onto the column and the flow through contains the unbound fraction. The bound fraction is separately eluted and collected (Paragraph [0015]). Additionally, the mixture is separated into at least two fractions using a technique that separates components of a mixture based on size, optionally, wherein the technique is size exclusion chromatography (Paragraph [0063]).
Bondarenko et al. do not explicitly state the stressed therapeutic proteins feature a PTM known to reduce binding.
However, Bondarenko et al. do disclose the therapeutic protein is placed in a condition that leads to a change in its structure, e.g, formation of one or more attributes, and the change in structure reduces the affinity of the therapeutic protein for its target (Paragraph [0040]). As such, the disclosure of Bondarenko et al. reads on the stressed therapeutic proteins feature a PTM known to reduce binding.
Regarding claim 21(d), Bondarenko et al. disclose for each of the unbound fraction and bound fraction, quantifying the abundance of the known structure (e.g., attribute) (Paragraph [0033]).
Regarding claim 21(e), Bondarenko et al. differ from instant claim 1(e) insofar as not explicitly disclosing comparing said amount to an amount quantitated in a control sample to determine enrichment. However, Bondarenko et al. do disclose the stress causes a reduced level of interactions between the therapeutic protein and its target. In some aspects, the stress causes an about 10% to about 50% reduction in interactions, relative to interactions in corresponding conditions lacking the stress (Paragraph [0055]). Considering a control sample is simply a sample that does not receive the experimental treatment, Bondarenko et al.’s disclosure of corresponding conditions lacking the stress reads on a control sample.
Regarding claim 21(f) and (g), Bondarenko et al. do not disclose repeating steps (a)-(e) using varied amounts of said protein of interest to said capture molecule or comparing an enrichment of said variant across amounts of step (f) to select an amount of protein of interest and capture molecule.
However, Shi et al. disclose a method for determining critical residues involved in antibody-target binding by size-exclusion chromatography (SEC) of competitive binding between a stressed antibody and its target followed by SEC fractionation and peptide mapping characterization of bound and unbound antibodies (See entire document, Abstract). More specifically, Shi et al. disclose using varied amounts of antibody, reading on a protein of interest, and receptor, reading on a capture molecule. Shi et al. disclose using a ratio of 1:2 antibody to receptor and a ratio of 1:1 antibody to receptor (Page 4, Right Column, 2nd Paragraph). Additionally, a smaller amount of the receptor was provided, the 1:1 ratio, to create a competitive binding environment where the unbound antibody can be present (Page 4, Right Column, 2nd Paragraph). As such, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used varying amounts of protein of interest and capture molecule and compared the enrichment between the differing amounts in the method of Bondarenko et al. motivated by the desire to create the ratio at which the desired amount of unbound antibody would be present as taught by Shi et al.
Regarding claim 22, Bondarenko et al. disclose the stressed antibody-receptor samples were also analyzed using SEC-UV-MALS to determine binding stoichiometry (Paragraph [00148]). SEC-UV-MALS is a combination of Size Exclusion Chromatography (SEC), UV (Ultraviolet) and Multi-Angle Light Scattering (MALS) detectors. As such, under the broadest reasonable interpretation, the disclosure of analyzing the antibody-receptor samples, which can include bound and unbound antibody, using SEC-UV-MALS, reads on determining an amount of bound to unbound protein of interest by measuring a concentration of bound and unbound protein of interest using a UV detector.
Regarding claim 23 and 35, Bondarenko et al. do not disclose wherein the amount of protein of interest and capture molecule is selected to produce about 50% bound and about 50% unbound protein of interest.
However, Shi et al. disclose when a ratio of 1:1 stressed antibody:receptor antibody mixture was used, about 40% of the stressed antibody remained unbound (Page 4, Right Column, 2nd Paragraph). About 40% of stressed antibody being unbound reads on about 50% unbound protein of interest.
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Additionally, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). As such, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have selected an amount of protein of interest and capture molecule to produce about 50% bound and about 50% unbound protein of interest in the method of Bondarenko et al. as that is a range disclosed by the prior art.
Regarding claim 24 and 36, Bondarenko et al. do not disclose wherein the relative amount of protein of interest and capture molecule is selected to produce about 90% bound and about 10% unbound protein of interest.
However, Shi et al. disclose when a ratio of 1:2 was used to generate antibody-receptor complex, ~96% of antibody formed a complex, reading on bound protein of interest, with two molecules of HER2 (Page 4, Right Column, 2nd Paragraph). About 96% of antibody forming a complex reads on about 90% bound protein of interest.
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. Additionally, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). As such, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have selected an amount of protein of interest and capture molecule to produce about 90% bound and about 10% unbound protein of interest in the method of Bondarenko et al. as that is a range disclosed by the prior art.
Response to Arguments
Applicant’s arguments filed 12/24/2025 have been fully considered but they are not persuasive.
Applicant’s arguments presented in the Request for Continued examination have been fully considered by the Examiner. It is the Examiner’s position that the amended claims are still obvious over the prior art of record as explained in the rejection set forth above. Additionally, Applicant’s arguments were addressed in the rejection set forth above.
Conclusion
Claims 1-24 and 35-37 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ASHLEY T WHITE whose telephone number is (571)272-0683. The examiner can normally be reached Monday - Friday 8:30 - 5:00 EST.
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/A.T.W./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653