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 .
DETAILED ACTION
Summary
This is a Non-Final Office action based on the 17/436218 RCE response filed on 06/02/2026.
Claims 1-3, 5-6, 8-9, 13-16, 18, 20, 23, 25-34, 39-42, 44-46 are pending and have been fully considered.
Claims 4, 7, 10-12, 17, 19, 21-22, 24, 35-38, 43, & 47-48 are cancelled.
Claim Interpretation
With respect to the instantly claimed “high molecular weight species,” of the therapeutic proteins, the instant specification discloses that these form or can form during each of the many steps that lead up to administration of a therapeutic protein (e.g., production, harvest, purification, formulation, storage and delivery). Further, these High Molecular Weight (HMW) species of therapeutic proteins are a concern for the biopharmaceutical industry from the standpoint of safety and efficacy, because HMW species can exhibit a reduced therapeutic efficacy and can lead to undesirable immunological responses once administered to patients (instant PGPUB specification paragraph 0003). Applicant’s instant method seems to be a method of assaying for the formation of high molecular weight (HMW) species of a therapeutic protein, in an environment which somewhat mimics in vivo conditions. This requires know the amount of or if there are any HMW species prior to placement in the conditions mimicking biological conditions, and also this requires knowing what is considered a “high,” molecular weight species versus what is not. Even further if calculation of “reversibility,” is done--- it is required to know what it is reversible from. Some of these points are further discussed in the 112 rejections below.
It is noted that “in vivo reversibility,” does not seem to be too common of a term used in the prior art. Methods for assaying for “vivo stability,” seem to be more common, and it would seem that vivo stability and vivo reversibility might be the opposite of one another.
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 1-3, 5-6, 8-9, 13-16, 18, 20, 23, 25-34, 39-42, 44-46 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1: Independent Claims 1, 39, 41, 44-45 are directed towards methods.
Step 2A, Prong One: Independent Claims 1, 39, 41, & 44-45 recite abstract ideas which are “calculating,” and also in some claims, “comparing,” the measured level of biomarker to the level in a control sample. Both calculating and comparing are mathematical processes and a mental processes which are abstract ideas.
Comparison is a mental process or at best, a mathematical comparison using an equation. Formulas or equations are mathematical concepts, which are an enumerated abstract idea (MPEP § 2106.04(a)). Further, as the determining in the preamble results in a calculation, the determining in this instance is also interpreted as calculating.
Step 2A, Prong Two: The abstract idea in independent Claims 1, 39, 41, and 44-45 are not integrated into a practical application because upon or after the calculating and comparing, nothing further is done to practically apply.
Also- the claimed measuring/determining steps, by SEC and affinity chromatography as instantly claimed as just data gathering to perform the judicial exceptions. Data gathering is considered to be extra-solution activity, and does not practically apply the judicial exception. See MPEP 2106.05 (g).
Step 2B: There is nothing in independent Claims 1, 39, 41, & 44-45 which add something which is non routine and conventional or significantly more to the claimed abstract idea judicial exception.
“Determining,” especially as generally claimed instantly claimed of HMW proteins, which include aggregated therapeutic proteins such as antibodies, by using SEC and affinity chromatography is well understood routine and conventional (WURC) in the art. So is using HMW species that are less than .1 micron in size or less.
This is evidenced by by WAGNER in US 20060003384.
WAGNER teaches of a method of assaying serum samples from patients using a therapeutic protein (infliximab) which is a recombinant antigenic protein (paragraph 0027), by size exclusion chromatography (HPLC-SEC) and other chromatography methods (paragraph 0009, 0024) to determine the presence or absences of high molecular weight species (paragraphs 0026, 0027, 0034-0036).
This is also evidenced by BOWEN- “Soluble aggregates of proteins are commonly analyzed using size exclusion chromatography.” (Page 7, paragraph 1).
See MPEP 2106.05(d)- “laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner.”
The dependent claims are analyzed the same way as above.
Claim 2-3, 5-6, 40, recites the size and size content of the HMW species. As is the case above, measuring compounds of this size is WURC. Therefore, this does nothing to practically apply at step 2A/2, nor to add significantly more at step 2B.
Claim 8 recites an equation, which is math and an abstract idea itself, therefore does to practically apply at step 2A/2, nor to add significantly more at step 2B.
Claims 13-16, 18, 20, 23 recites what the content of the serum and therapeutic protein are. These elements carry the same analysis as in the independent claim so does nothing to practically, apply at step 2A/2, nor to add significantly more at step 2B.
Claims 25-27, 32-34, 42, 46 specifies that the which is SEC is a more specific type of SEC, or affinity chromatography and how is carried out however this is still WRUC and also used for data gathering so does not practically apply at step 2A/2, nor to add significantly more at step 2B.
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 non-obviousness.
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.
Claim(s) 1-3, 5-6, 8-9, 13, 18, 20, 23 & 25-27, 41 is/are rejected under 35 U.S.C. 103 as being obvious by WAGNER in US 20060003384 in view of and further in view ROBERTS in Protein aggregation and its impact on product quality in view of BOWEN in A Multi-particulate delivery system for potential colonic targeting using bovine serum albumin as a model protein (as cited on IDS dated 11/15/2021).
With respect to Claim 1, WAGNER teaches of a method of assaying serum samples from patients using a therapeutic protein (infliximab) which is a recombinant antigenic protein (paragraph 0027), by size exclusion chromatography (HPLC-SEC) and other chromatography methods (paragraph 0009, 0024) to determine the presence or absences of high molecular weight species (paragraphs 0026, 0027, 0034-0036).
Specifically, WAGNER teaches of a method for detecting and/or measuring serum antibodies to antigenic proteins in a sample, comprising adding a labeled antigenic protein or fragment thereof to a sample derived from serum and expected to contain serum antibodies and measuring differences in at least one characteristic between (a) a labeled serum antibody-antigenic protein complex; (b) an serum antibody-antigenic protein complex in the sample; and/or (c) displaced labeled or unlabeled serum antibody, antigenic protein or fragment thereof (abstract).
WAGNER further teaches that the label induced antibody-antigenic protein complex is a high molecular weight species and that it is distinguished or resolved from unlabeled protein complex by size exclusion chromatography, and that the label induced antibody-antigenic protein complex is detected based on the molecular size, label, tag, and amplification of the label or tag, and ability to bind to a detectable substrate (paragraph 0009). WAGNER teaches of labeling the antigenic protein (therapeutic protein) (abstract, paragraph 0002, 0008-0009), and that the labels can be fluorescent (paragraph 0024, 0025).
WAGNER specifically teaches of using as serum sample and of incubating the serum sample and the therapeutic protein (infliximab) (paragraph 0015-0020). Since a serum sample is taken—this is a method for in-vitro assaying of in vivo levels. Therefore, this reads on steps a) and b) of Claim 1 as instantly claimed. Further—since these are the only steps claimed, and determining the “in vivo reversibility,” as claimed for Claim 1, seems to only be done by a) incubating as claimed and then by b) determining the level of HMW species at timepoints after a)….since WAGNER teaches of steps a) & b), it makes the instant determination go in vivo reversibility obvious.
WAGNER does not teach that the therapeutic protein is an antibody or antigen binding fragment of a bispecific T-cell engager molecule or a chimeric antigen receptor (CAR), nor of determining a measure of or controlling reversibility in vivo.
ROBERTS is used to remedy this and teaches of measuring and detecting protein pharmaceutical products which are antibodies (abstract). ROBERTS further teaches that the protein antibodies form aggregates (HMW species (Page 212, column 1 paragraph 1) and that this impacts product quality (Page 213m column 2m last paragraph). Even further, ROBERTS teaches of controlling aggregation by adjusting pH and salt concentration, and of also controlling the aggregation with respect to in vivo conditions (Page 214, column 2, second paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to detect/determine to control the reversibility as is done in ROBERTS in the method of WAGNER due to the negative impacts aggregation (HMW proteins) has with respect to having limited solubility and delivery capabilities and therefore its effectiveness as a therapeutic therefore the need to see if the aggregates are reversible (ROBERTS, Page 213, column 1, last paragraph).
WAGNER and ROBERTS do not use the term “in vivo reversibility,” though it is shown above how they teach of the steps needed to perform the claimed calculation and why one would want to look for reversibility of HMW (aggregates) of therapeutic proteins, which makes the claimed determination of in vivo reversibility obvious. Further, if it is unclear that WAGNER and ROBERTS teach of assaying before incubation (knowing the level of HMW species before incubation, or that the HMW specifically comprises non-covalently bonded aggregates (proteins being a “mer,” structure/unit bigger than a dimer, trimer). Further- they do not teach of the claimed size of “less than 1 micron,” or of the claimed equation for calculation of HMW species/aggregates or reversibility thereof.
BOWEN is used to remedy this and teaches of calculating insoluble (irreversible) aggregates which is the concentration of protein in solution-concentration of filtrate divided by the concentration of protein solution, then times 100% (Page 4). BOWEN teaches of using bovine serum albumin as a model for protein aggregation and study of protein drug products (therapeutic proteins). BOWEN teaches that the insoluble aggregates might not have the same biological potency as a monomer/ non aggregates (Page 7, paragraph 2).
BOWEN further teaches of the proteins having a monomer structure (Page 7, paragraph 2), and of monitoring the level of monomer, dimer, trimer aggregates by chromatograph (so the level is known- can comparison can be made to known amount) and that sometimes this aggregation is reversible meaning the bonding is reversible/non-covalent (dimer would have one bond, timer would have two bonds) (Page 5, first paragraph, Page 7, paragraph 2).
BOWEN also teaches of assaying before incubation (knowing the level of HMW species prior to incubation) (Page 8, bottom paragraph, Page 9, top paragraph).
BOWEN further teaches of the protein particles being 100 nm, which reads on “less that .1 micron,” through broadest reasonable interpretation, and further teaches of particles being 3.3-4.3 nm (Page 8, paragraph 3, last 2 lines). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to optimize protein size to the size used in BOWEN in the method of WAGNER due to the affect protein size has on aggregation and the need in the art to monitor and adjust for aggregation based on protein size (BOWEN, Page 7, paragraph 2, 5 lines from bottom).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to optimize protein structure to the structures used in BOWEN in the method of WAGNER and ROBERTS due to the affect protein size has on aggregation and the need in the art to monitor and adjust for aggregation based on protein structure (BOWEN, Page 7, paragraph 2, 5 lines from bottom).
It would have been obvious to assay before and after incubation due to the advantage this would offer for performing a deconvolution/secondary structure analysis (Page 8, bottom paragraph, Page 9, top paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to optimize detection of vivo reversibility versus irreversibility and calculate as is done in BOWEN in the method of WAGNER and ROBERTS due to the affect protein size has on aggregation and the need in the art to monitor and adjust for aggregation based on protein size due to the affect this has on drug efficacy (BOWEN, Page 7, paragraph 2).
With respect to Claim 2, WAGNER and ROBERTS teach of the invention as shown above for claim 1, but do not call out the size in nanometers of the HMW species.
BOWEN is used to remedy this. BOWEN teaches of methods of delivering therapeutic proteins for treatment of diseases using multi-particulate beads (Abstract, purpose). BOWEN further teaches of the protein particles being 100 nm, which reads on “about 99nm,” through broadest reasonable interpretation, and further teaches of particles being 3.3-4.3 nm, which can read on “about 10 nm,” through broadest reasonable interpretation (Page 8, paragraph 3, last 2 lines). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to optimize protein size to the size used in BOWEN in the method of WAGNER and ROBERTS due to the affect protein size has on aggregation and the need in the art to monitor and adjust for aggregation based on protein size (BOWEN, Page 7, paragraph 2, 5 lines from bottom).
With respect to Claim 3, WAGNER does not teach of the protein comprising a mer structure bigger than monomer. BOWEN is used to remedy this and further teaches of the proteins having monomer, dimer, trimer structure (Page 7, paragraph 2).
It would have been obvious to one of ordinary skill in the art to optimize protein structure to the structures used in BOWEN in the method of WAGNER and ROBERTS due to the affect protein size has on aggregation and the need in the art to monitor and adjust for aggregation based on protein structure (BOWEN, Page 7, paragraph 2, 5 lines from bottom).
With respect to Claim 5, WAGNER does not teach of the proteins being a “mer,” structure/unit bigger than monomer. BOWEN is used to remedy this and further teaches of the proteins having monomer, dimer, trimer structure (Page 7, paragraph 2), and of monitoring the level of monomer, dimer, trimer by chromatograph (so the level is known) (Page 5, first paragraph).
It would have been obvious to one of ordinary skill in the art to optimize protein structure to the structures used in BOWEN in the method of WAGNER and ROBERTS due to the affect protein size has on aggregation and the need in the art to monitor and adjust for aggregation based on protein structure (BOWEN, Page 7, paragraph 2, 5 lines from bottom).
With respect to Claim 6, WAGNER does not teach of the proteins being a “mer,” structure/unit bigger than dimer, trimer, or of assaying for the levels of “mers”. BOWEN is used to remedy this and further teaches of the proteins having monomer structure (Page 7, paragraph 2), and of monitoring the level of monomer, dimer, trimer by chromatograph (so the level is known) (Page 5, first paragraph).
It would have been obvious to one of ordinary skill in the art to optimize protein structure to the structures used in BOWEN in the method of WAGNER and ROBERTS due to the affect protein size has on aggregation and the need in the art to monitor and adjust for aggregation based on protein structure (BOWEN, Page 7, paragraph 2, 5 lines from bottom).
With respect to Claim 8, BOWEN teaches of calculating insoluble aggregates which is the concentration of protein in solution-concentration of filtrate divided by the concentration of protein solution, then times 100% (Page 4). As Claim 8 is unclear- this teaching makes what is instantly claimed for calculating the in vivo reversibility by % of HMW in mixture over HMW in sample obvious.
With respect to Claim 9, WAGNER teaches of incubation of serum and infliximab for 1 hour (paragraph 0033, 0035-0039, 0043-0044).
With respect to Claim 13, WAGNER teaches of infliximab being present at a concentration of 15.3 ug/ml in the serum sample mixture (paragraph 0027). This concentration level falls within the claimed range of 10ug/ml to 300ug/ml.
With respect to Claim 18, WAGNER teaching of using a whole blood sample (which can also be considered whole serum as serum in a component of blood) (paragraph 0008).
With respect to Claim 20, WAGNER teaches of using human serum (paragraph 0027 & 0032). WAGNER teaching of using a whole blood sample (which can also be considered whole serum as serum in a component of blood) (paragraph 0008).
With respect to Claim 23, WAGNER teaches of a dilution step (paragraph 0041) which can be considered after step a and any time period can be incubation period before step b.
With respect to Claim 25, WAGNER teaches of using HPLC-SEC (paragraph 0009).
With respect to Claim 26, WAGNER teaches of incubation, then separation, then detection (so separation between incubation and assaying) (paragraphs 0012-0020, 0043-0044, & 0024).
With respect to Claim 27, WAGNER teaches of separation by HPLC (high performance liquid chromatography) (paragraphs, 0009 0012-0020, 0043-0044, & 0024).
With respect to Claim 41, WAGNER teaches of a method of assaying serum samples from patients using a therapeutic protein (infliximab), by size exclusion chromatography to determine the presence or absences of high molecular weight species (paragraphs 0026, 0027, 0034-0036).
Specifically, WAGNER teaches of a method for detecting and/or measuring serum antibodies to antigenic proteins in a sample, comprising adding a labeled antigenic protein or fragment thereof to a sample derived from serum and expected to contain serum antibodies and measuring differences in at least one characteristic between (a) a labeled serum antibody-antigenic protein complex; (b) an serum antibody-antigenic protein complex in the sample; and/or (c) displaced labeled or unlabeled serum antibody, antigenic protein or fragment thereof (abstract).
WAGNER further teaches that the label induced antibody-antigenic protein complex is a high molecular weight species and that it is distinguished or resolved from unlabeled protein complex by size exclusion chromatography, and that the label induced antibody-antigenic protein complex is detected based on the molecular size, label, tag, and amplification of the label or tag, and ability to bind to a detectable substrate (paragraph 0009).
WAGNER specifically teaches of using as serum sample and of incubating the serum sample and the therapeutic protein (infliximab) (paragraph 0015-0020). Since a serum sample is taken—this is a method for in-vitro assaying of in vivo levels.
WAGNER does not teach that the therapeutic protein is an antibody or antigen binding fragment of a bispecific T-cell engager molecule or a chimeric antigen receptor (CAR), nor of determining or controlling reversibility in vivo.
ROBERTS is used to remedy this and teaches of measuring and detecting protein pharmaceutical products which are antibodies (abstract). ROBERTS further teaches that the protein antibodies form aggregates (HMW species (Page 212, column 1 paragraph 1) and that this impacts product quality (Page 213m column 2m last paragraph). Even further, ROBERTS teaches of controlling aggregation by adjusting pH and salt concentration, and of also controlling the aggregation with respect to in vivo conditions (Page 214, column 2, second paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to detect/determine to control the reversibility as is done in ROBERTS in the method of WAGNER due to the negative impacts aggregation (HMW proteins) has with respect to having limited solubility and delivery capabilities and therefore its effectiveness as a therapeutic (ROBERTS, Page 213, column 1, last paragraph).
WAGNER and ROBERTS do not use the term “in vivo reversibility,” though it is shown above how they teach oft the steps needed to perform the claimed calculation. Further, if it is unclear that WAGNER and ROBERTS teach of assaying before incubation (knowing the level of HMW species before incubation, or that the HMW specifically comprises non-covalently bonded aggregates (proteins being a “mer,” structure/unit bigger than a dimer, trimer). Further- they do not teach of the claimed size of “less than 1 micron.”
BOWEN teaches of calculating insoluble aggregates which is the concentration of protein in solution-concentration of filtrate divided by the concentration of protein solution, then times 100% (Page 4). BOWEN further teach of monitoring the level of monomer, dimer, trimer aggregates by chromatograph (so the level is known- and comparison can be made to known amount) and that sometimes this aggregation is reversible meaning the bonding is reversible/non-covalent (dimer would have one bond, timer would have two bonds) (Page 5, first paragraph, Page 7, paragraph 2). It would have been obvious to one of ordinary skill in the art to optimize detection of vivo reversibility and calculate as is done in BOWEN in the method of WAGNER and ROBERTS due to the affect protein size has on aggregation and the need in the art to monitor and adjust for aggregation based on protein size (BOWEN, Page 7, paragraph 2, 5 lines from bottom).
Claim(s) 14-16, 28-34, 42, & 45-46 is/are rejected under 35 U.S.C. 103 as being obvious by WAGNER in US 20060003384 in view of and further in view ROBERTS in Protein aggregation and its impact on product quality in view of BOWEN in A Multi-particulate delivery system for potential colonic targeting using bovine serum albumin as a model protein (as cited on IDS dated 11/15/2021) and further in view of BOSCHETTI in US 20060216751.
With respect to Claim 14, WAGNER teaches of the claimed invention as shown above. WAGNER further teaches of using the antigenic protein to monoclonal antigenic protein in a ratio of 3:1(paragraph 0027), but do not teach of using depleted serum. Therefore- this is a teaching of the mixture being 100% serum then mixing the other compounds in it. WAGNER does not teach of using depleted serum.
BOSCHETTI is used to remedy this and teaches of a method of purifying and using a target protein group (abstract) and of assessing the target protein purity through assays (paragraph 0164). BOSCHETTI teaches that the detection can be done by size exclusion chromatography (paragraph 0009, 0026). BOSCHETTI teaches of using affinity chromatography (paragraph 0005-0008) and of using binding moieties that can use antibodies (paragraph 0042, 0091, 0104, 0177). BOSCHETTI further teaches that the target protein group is a therapeutic protein (paragraph 0050), that the therapeutic protein may be a chimeric antibody and further that the antibody can be bispecific and that the therapeutic protein can comprise a protein receptor or T-cell receptor (paragraph 0052, 0054, 0053, 0029, 0014, 0023, 0048).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to assess therapeutic protein as is done in BOSCHETTI in the method of WAGNER due to the advantage therapeutic proteins such as these have with respect to eliciting a response when administered to a patient suffering from a disease (BOSCHETTI, paragraph 0050) and it would have been obvious to one to detect these as is done on BOSCHETTI in the methods of WAGNER and ROBERTS due to use size exclusion chromatography for detection due to the advantage it has shown for distinguishing or identifying compounds ( BOSCHETTI, paragraph 0009).
BOSCHETTI teach of methods of purifying proteins (abstract), and of using serum (paragraph 0003), and of purposefully depletion certain analytes (serum depletion) and that the manipulation can happen in a variety of ways and is optimizable (paragraph 0176, 0195). It would have been obvious to one of ordinary skill in the art to optimize the % serum/serum depletion and therefore the % target protein as is done in BOSCHETTI in the methods of WAGNER due the advantage this offers in improving the purity of the target protein (BOSCHETTI, paragraph 0176).
With respect to Claim 15, WAGNER and ROBERTS teach of the above, but do not teach as BOSCHETTI teaches of the binding moiety (paragraph 0029), which could be part of the depletion being IgG (paragraph 0003, 0176, 0195). See reason for combination from Claim 14.
With respect to Claim 16, WAGNER and ROBERTS teach of the above, but do not teach as BOSCHETTI teaches of depleting the samples and of manipulating/adjusting what is determined to be needed to deplete (paragraph 0176). Therefore- though BOSCHETTI does not call out depleting the samples from compounds with a particular kDa level, it would have been obvious to one of ordinary skill to optimize this by routine experimentation. (In re Boesch, 617 F.2d. 272, 205 USPQ 215 (CCPA 1980)), since it has been held that where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. (In re Aller, 105 USPQ 223). “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The discovery of an optimum value of a known result effective variable, without producing any new or unexpected results, is within the ambit of a person of ordinary skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980) (see MPEP § 2144.05, II.). “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The discovery of an optimum value of a known result effective variable, without producing any new or unexpected results, is within the ambit of a person of ordinary skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980) (see MPEP § 2144.05, II.). See reason for combination from Claim 14.
With respect to Claim 28, WAGNER and ROBERTS teach of the above, but do not teach as BOSCHETTI teaches of using affinity chromatography (paragraph 0005-0008) and of using binding moieties that can use antibodies(paragraph 0042, 0091, 0104, 0177). See reason for combination from Claim 14.
With respect to Claim 29, WAGNER and ROBERTS teach of the above, but do not teach as BOSCHETTI teaches of using acidic elution buffers, including HCL (paragraph 0154-0155 & Table 1). See reason for combination from Claim 14.
With respect to Claim 30, WAGNER and ROBERTS teach of the above, but do not teach as BOSCHETTI teaches of using acidic elution buffers, including glycine (paragraph 0154-0155 & Table 1). See reason for combination from Claim 14.
With respect to Claim 31, WAGNER and ROBERTS teach of the above, but do not teach as BOSCHETTI teaches of using acidic elution buffers, which have pH of 2.5 and 3.5 (paragraph 0154-0155 & Table 1). See reason for combination from Claim 14.
With respect to Claim 32, WAGNER and ROBERTS teach of the above, but do not teach as BOSCHETTI teaches of using acidic elution buffers, which have pH of 2.5 and 3.5 (paragraph 0154-0155 & Table 1). See reason for combination from Claim 14.
With respect to Claim 33, WAGNER and ROBERTS teach of the above, but do not teach as BOSCHETTI teaches of eluting the proteins by using a buffer/eluting agent (Table 1, paragraph 0005, 0039, 0122). See reason for combination from Claim 14.
With respect to Claim 34, WAGNER and ROBERTS teach of the above, but do not teach as BOSCHETTI teaches of using a resin for chromatography and incubation (sitting with) the resin (paragraph 0005, 0086-0087). See reason for combination from Claim 14.
With respect to Claim 42, WAGNER and ROBERTS teach of the above, but do not teach as BOSCHETTI teaches of the protein being Protein A (paragraph 0054). See reason for combination from Claim 14.
With respect to Claim 45, WAGNER teaches of a method of assaying serum samples from patients using a therapeutic protein (infliximab), by size exclusion chromatography to determine the presence or absences of high molecular weight species (paragraphs 0026, 0027, 0034-0036).
Specifically, WAGNER teaches of a method for detecting and/or measuring serum antibodies to antigenic proteins in a sample, comprising adding a labeled antigenic protein or fragment thereof to a sample derived from serum and expected to contain serum antibodies and measuring differences in at least one characteristic between (a) a labeled serum antibody-antigenic protein complex; (b) an serum antibody-antigenic protein complex in the sample; and/or (c) displaced labeled or unlabeled serum antibody, antigenic protein or fragment thereof (abstract).
WAGNER further teaches that the label induced antibody-antigenic protein complex is a high molecular weight species and that it is distinguished or resolved from unlabeled protein complex by size exclusion chromatography, and that the label induced antibody-antigenic protein complex is detected based on the molecular size, label, tag, and amplification of the label or tag, and ability to bind to a detectable substrate (paragraph 0009).
WAGNER specifically teaches of using as serum sample and of incubating the serum sample and the therapeutic protein (infliximab) (paragraph 0015-0020). Since a serum sample is taken—this is a method for in-vitro assaying of in vivo levels.
WAGNER does not call out the calculation of vivo reversibility or of non-covalent bonds.
WAGNER does not teach that the therapeutic protein is an antibody or antigen binding fragment of a bispecific T-cell engager molecule or a chimeric antigen receptor (CAR), nor of determining a measure of or controlling reversibility in vivo.
ROBERTS is used to remedy this and teaches of measuring and detecting protein pharmaceutical products which are antibodies (abstract). ROBERTS further teaches that the protein antibodies form aggregates (HMW species (Page 212, column 1 paragraph 1) and that this impacts product quality (Page 213m column 2m last paragraph). Even further, ROBERTS teaches of controlling aggregation by adjusting pH and salt concentration, and of also controlling the aggregation with respect to in vivo conditions (Page 214, column 2, second paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to detect/determine to control the reversibility as is done in ROBERTS in the method of WAGNER due to the negative impacts aggregation (HMW proteins) has with respect to having limited solubility and delivery capabilities and therefore its effectiveness as a therapeutic therefore the need to see if the aggregates are reversible (ROBERTS, Page 213, column 1, last paragraph).
WAGNER and ROBERTS do not use the term “in vivo reversibility,” though it is shown above how they teach of the steps needed to perform the claimed calculation and why one would want to look for reversibility of HMW (aggregates) of therapeutic proteins, which makes the claimed determination of in vivo reversibility obvious. Further, if it is unclear that WAGNER and ROBERTS teach of assaying before incubation (knowing the level of HMW species before incubation, or that the HMW specifically comprises non-covalently bonded aggregates (proteins being a “mer,” structure/unit bigger than a dimer, trimer). Further- they do not teach of the claimed size of “less than 1 micron,” or of the claimed equation for calculation of HMW species/aggregates or reversibility thereof.
BOWEN teaches of calculating insoluble aggregates which is the concentration of protein in solution-concentration of filtrate divided by the concentration of protein solution, then times 100% (Page 4). BOWEN further teach of monitoring the level of monomer, dimer, trimer aggregates by chromatograph (so the level is known- and comparison can be made to known amount) and that sometimes this aggregation is reversible meaning the bonding is reversible/non-covalent (dimer would have one bond, timer would have two bonds)(Page 5, first paragraph, Page 7, paragraph 2). It would have been obvious to one of ordinary skill in the art to optimize detection of vivo reversibility and calculate as is done in BOWEN in the method of WAGNER due to the affect protein size has on aggregation and the need in the art to monitor and adjust for aggregation based on protein size (BOWEN, Page 7, paragraph 2, 5 lines from bottom).
BOSCHETTI is used to remedy this and teaches of a method of purifying and using a target protein group (abstract) and of assessing the target protein purity through assays (paragraph 0164). BOSCHETTI further teaches that the target protein group is a therapeutic protein (paragraph 0050), that the therapeutic protein may be a chimeric antibody and further that the antibody can be bispecific and that the therapeutic protein can comprise a protein receptor or T-cell receptor (paragraph 0052, 0054, 0053, 0029, 0014, 0023, 0048). BOSCHETTI teaches of depleting the samples and of manipulating/adjusting what is determined to be needed to deplete (paragraph 0176). of the binding moiety (paragraph 0029), which could be part of the depletion being IgG (paragraph 0003, 0176, 0195). BOSCHETTI further teaches of depleting of certain analytes (which would have certain molecular weight) (paragraph 0176, 0195). BOSCHETTI teaches of using affinity chromatography (paragraph 0005-0008) and of using binding moieties that can use antibodies (paragraph 0042, 0091, 0104, 0177).
It would have been obvious to one of ordinary skill in the art to assess the therapeutic protein of BOSCHETTI in the method of WAGNER due to the advantage therapeutic proteins such as these have with respect to eliciting a response when administered to a patient suffering from a disease (BOSCHETTI, paragraph 0050).
With respect to Claim 46, WAGNER teaches of the capture molecule being an antibody (paragraph 0009).
Claim(s) 39-40, 44 is/are rejected under 35 U.S.C. 103 as being unpatentable over WAGNER in US 20060003384 in view ROBERTS in Protein aggregation and its impact on product quality in view of BOSCHETTI in US 20060216751 and further in view of BOTTI in US 20090220452 and further in view of BOWEN in A Multi-particulate delivery system for potential colonic targeting using bovine serum albumin as a model protein (as cited on IDS dated 11/15/2021).
With respect to Claim 39, WAGNER teaches of a method of assaying serum samples from patients using a therapeutic protein (infliximab), by size exclusion chromatography to determine the presence or absences of high molecular weight species (paragraphs 0026, 0027, 0034-0036).
Specifically, WAGNER teaches of a method for detecting and/or measuring serum antibodies to antigenic proteins in a sample, comprising adding a labeled antigenic protein or fragment thereof to a sample derived from serum and expected to contain serum antibodies and measuring differences in at least one characteristic between (a) a labeled serum antibody-antigenic protein complex; (b) an serum antibody-antigenic protein complex in the sample; and/or (c) displaced labeled or unlabeled serum antibody, antigenic protein or fragment thereof (abstract).
WAGNER further teaches that the label induced antibody-antigenic protein complex is a high molecular weight species and that it is distinguished or resolved from unlabeled protein complex by size exclusion chromatography, and that the label induced antibody-antigenic protein complex is detected based on the molecular size, label, tag, and amplification of the label or tag, and ability to bind to a detectable substrate (paragraph 0009).
WAGNER specifically teaches of using as serum sample and of incubating the serum sample and the therapeutic protein (infliximab) (paragraph 0015-0020). Since a serum sample is taken—this is a method for in-vitro assaying of in vivo levels.
WAGNER does not teach that the therapeutic protein is an antibody or antigen binding fragment of a bispecific T-cell engager molecule or a chimeric antigen receptor (CAR), nor of determining a measure of or controlling reversibility in vivo.
ROBERTS is used to remedy this and teaches of measuring and detecting protein pharmaceutical products which are antibodies (abstract). ROBERTS further teaches that the protein antibodies form aggregates (HMW species (Page 212, column 1 paragraph 1) and that this impacts product quality (Page 213m column 2m last paragraph). Even further, ROBERTS teaches of controlling aggregation by adjusting pH and salt concentration, and of also controlling the aggregation with respect to in vivo conditions (Page 214, column 2, second paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to detect/determine to control the reversibility as is done in ROBERTS in the method of WAGNER due to the negative impacts aggregation (HMW proteins) has with respect to having limited solubility and delivery capabilities and therefore its effectiveness as a therapeutic therefore the need to see if the aggregates are reversible (ROBERTS, Page 213, column 1, last paragraph).
WAGNER and ROBERTS do not use the term “in vivo reversibility,” though it is shown above how they teach of the steps needed to perform the claimed calculation and why one would want to look for reversibility of HMW (aggregates) of therapeutic proteins, which makes the claimed determination of in vivo reversibility obvious. Further, if it is unclear that WAGNER and ROBERTS teach of assaying before incubation (knowing the level of HMW species before incubation, or that the HMW specifically comprises non-covalently bonded aggregates (proteins being a “mer,” structure/unit bigger than a dimer, trimer). Further- they do not teach of the claimed size of “less than 1 micron,” or of the claimed equation for calculation of HMW species/aggregates or reversibility thereof.
WAGNER and ROBERTS do no teach of using depleted serum.
BOSCHETTI is used to remedy this and teaches of a method of purifying and using a target protein group (abstract) and of assessing the target protein purity through assays (paragraph 0164). BOSCHETTI further teaches that the target protein group is a therapeutic protein (paragraph 0050), that the therapeutic protein may be a chimeric antibody and further that the antibody can be bispecific and that the therapeutic protein can comprise a protein receptor or T-cell receptor (paragraph 0052, 0054, 0053, 0029, 0014, 0023, 0048). BOSCHETTI teaches of depleting the samples and of manipulating/adjusting what is determined to be needed to deplete (paragraph 0176). of the binding moiety (paragraph 0029), which could be part of the depletion being IgG (paragraph 0003, 0176, 0195). BOSCHETTI further teaches of depleting of certain analytes (which would have certain molecular weight) (paragraph 0176, 0195). BOSCHETTI teaches of using affinity chromatography (paragraph 0005-0008) and of using binding moieties that can use antibodies (paragraph 0042, 0091, 0104, 0177).
It would have been obvious to one of ordinary skill in the art to assess the therapeutic protein of BOSCHETTI in the method of WAGNER due to the advantage therapeutic proteins such as these have with respect to eliciting a response when administered to a patient suffering from a disease (BOSCHETTI, paragraph 0050).
WAGNER and BOSCHETTI do not call out that the method is for determining in vivo reversibility of the therapeutic compound or of depleting specifically molecules having a pre-selected molecular weight range.
BOTTI is used to remedy this and specifically teaches of esterification of a protein or polypeptide compound (abstract) and that the protein/polypeptides is used as a therapeutic compounds (paragraph 0085). BOTTI further teaches of detecting in vivo reversibility of the ester bond (paragraph 0005, 0010, 0018,0099). BOTTI further teach of detecting compounds that have a kDa of 1,350-670,000 (which reads on 300 kDa or higher) (and excluding other molecules during a time—which through BRI can be considered an incubation time)(Page 5, paragraph 1). It would have been obvious to one of ordinary skill in the art to measure the in vivo reversibility of the protein therapeutic compound as is done in BOTTI in the method WAGNER and BOSCHETTI due to the need in the art for improved pharmacological properties in proteins (BOTTI, paragraph 0003).
WAGNER, ROBERTS, BOSCHETTI, and BOTTI does not teach of calculating percentages for in vivo reversibility or of the non-covalent bond of the aggregates. BOWEN make this obvious (Page 8, bottom paragraph, Page 9, top paragraph). BOWEN further teaches of calculating insoluble aggregates which is the concentration of protein in solution-concentration of filtrate divided by the concentration of protein solution, then times 100% (Page 4). BOWEN further teach of monitoring the level of monomer, dimer, trimer aggregates by chromatograph (so the level is known- and comparison can be made to known amount) and that sometimes this aggregation is reversible meaning the bonding is reversible/non-covalent (dimer would have one bond, timer would have two bonds)(Page 5, first paragraph, Page 7, paragraph 2).
It would have been obvious to one of ordinary skill before the effective filing date of the instant invention to calculate a percentage of the reversible bonds (in vivo reversibility) and binding functions after assaying due to the advantage this gives in providing useful information of the therapeutic compounds (Page 8, bottom paragraph, Page 9, top paragraph).
With respect to Claim 40, WAGNER teaches the infliximab being the therapeutic protein which has a molecular weight of 149 kDa which reads on 15 kDa or higher paragraphs 0026, 0027, 0034-0036).
With respect to Claim 44, WAGNER teaches of a method of assaying serum samples from patients using a therapeutic protein (infliximab), by size exclusion chromatography to determine the presence or absences of high molecular weight species (paragraphs 0026, 0027, 0034-0036).
Specifically, WAGNER teaches of a method for detecting and/or measuring serum antibodies to antigenic proteins in a sample, comprising adding a labeled antigenic protein or fragment thereof to a sample derived from serum and expected to contain serum antibodies and measuring differences in at least one characteristic between (a) a labeled serum antibody-antigenic protein complex; (b) an serum antibody-antigenic protein complex in the sample; and/or (c) displaced labeled or unlabeled serum antibody, antigenic protein or fragment thereof (abstract).
WAGNER further teaches that the label induced antibody-antigenic protein complex is a high molecular weight species and that it is distinguished or resolved from unlabeled protein complex by size exclusion chromatography, and that the label induced antibody-antigenic protein complex is detected based on the molecular size, label, tag, and amplification of the label or tag, and ability to bind to a detectable substrate (paragraph 0009).
WAGNER specifically teaches of using as serum sample and of incubating the serum sample and the therapeutic protein (infliximab) (paragraph 0015-0020). Since a serum sample is taken—this is a method for in-vitro assaying of in vivo levels.
WAGNER does not teach that the therapeutic protein is an antibody or antigen binding fragment of a bispecific T-cell engager molecule or a chimeric antigen receptor (CAR).
BOSCHETTI is used to remedy this and teaches of a method of purifying and using a target protein group (abstract) and of assessing the target protein purity through assays (paragraph 0164). BOSCHETTI further teaches that the target protein group is a therapeutic protein (paragraph 0050), that the therapeutic protein may be a chimeric antibody and further that the antibody can be bispecific and that the therapeutic protein can comprise a protein receptor or T-cell receptor (paragraph 0052, 0054, 0053, 0029, 0014, 0023, 0048). BOSCHETTI teaches of the binding moiety (paragraph 0029), which could be part of the depletion being IgG (paragraph 0003, 0176, 0195). It would have been obvious to one of ordinary skill in the art to assess the therapeutic protein of BOSCHETTI in the method of WAGNER due to the advantage therapeutic proteins such as these have with respect to eliciting a response when administered to a patient suffering from a disease (BOSCHETTI, paragraph 0050).
WAGNER and BOSCHETTI does not call out that the method is for determining in vivo reversibility of the therapeutic compound or of fluorescent labels.
BOTTI is used to remedy this and specifically teaches of esterification of a protein or polypeptide compound (abstract) and that the protein/polypeptides is used as a therapeutic compounds (paragraph 0085). BOTTI further teaches of detecting in vivo reversibility of the ester bond (paragraph 0005, 0010, 0018,0099). BOTTI further teach of detecting compounds that have a kDa of 1,350-670,000 (which reads on 300 kDa or higher) (Page 5, paragraph 1), BOTTI teaches of using rhodamine as a fluorescent label (paragraph 0032-0033). It would have been obvious to one of ordinary skill in the art to measure the in vivo reversibility of the protein therapeutic compound as is done in BOTTI in the method WAGNER and BOSCHETTI due to the need in the art for improved pharmacological properties in proteins (BOTTI, paragraph 0003).
It would have been obvious to one of ordinary skill in the art to measure the in vivo reversibility of the protein therapeutic compound as is done in BOTTI in the method WAGNER due to the need in the art for improved pharmacological properties in proteins (BOTTI, paragraph 0003).
WAGNER does not teach of calculating percentages or of non-covlent/reversible bonds. BOWEN does (Page 8, bottom paragraph, Page 9, top paragraph)
BOWEN is used to remedy this. BOWEN teaches of methods of delivering therapeutic proteins for treatment of diseases using multiparticulate beads (Abstract, purpose). BOWEN further teaches of the protein particles being 100 nm, which reads on “about 99nm,” through broadest reasonable interpretation, and further teaches of particles being 3.3-4.3 nm, which can read on “about 10 nm,” through broadest reasonable interpretation (Page 8, paragraph 3, last 2 lines). BOWEN further teach of monitoring the level of monomer, dimer, trimer aggregates by chromatograph (so the level is known- and comparison can be made to known amount) and that sometimes this aggregation is reversible meaning the bonding is reversible/non-covalent (dimer would have one bond, timer would have two bonds)(Page 5, first paragraph, Page 7, paragraph 2).It would have been obvious to one of ordinary skill in the art to optimize protein size to the size used in BOWEN in the method of WAGNER due to the affect protein size has on aggregation and the need in the art to monitor and adjust for aggregation based on protein size (BOWEN, Page 7, paragraph 2, 5 lines from bottom).
BOWEN further teaches of calculating insoluble aggregates which is the concentration of protein in solution-concentration of filtrate divided by the concentration of protein solution, then times 100% (Page 4). As Claim 8 is unclear- this teaching makes what is instantly claimed for calculating the in vivo reversibility by % of HMW in mixture over HMW in sample obvious.
It would have been obvious to calculate a percentage (in vivo reversibility) and binding functions after assaying due to the advantage this gives in providing useful information of the therapeutic compounds and due to the advantage this haves in providing information about the protein structures (Page 8, bottom paragraph, Page 9, top paragraph).
Response to Arguments
Applicant's arguments filed 06/02/2026 have been fully considered but they are not persuasive.
The instant action is made Non-Final. This is notably, to add 101 rejection, which were not made in the prior Non-Final action, and is now made after consultation with SPE.
The prior 112 rejections were overcome. The examiner’s SPE was also consulted on this matter. The examiner notes that applicants instant amendments were helpful in overcome the other 112 rejections.
With respect to the prior art, applicant does not present substantive arguments about the prior art.
All claims remain rejected.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
KIM in US 20200064353
KIM teaches of therapeutic proteins pharmaceuticals aggregating during shipment and handling (paragraph 0006) and that the aggregates can be reversible (paragraph 0010-0011, 0154).
PATTON in US 20130137112
PATTON teaches of aggregating therapeutic proteins and determining if they are reversible (paragraph 0010-0011, 0014, 0050, 0170).
CORREIA in WO 2011091398
CORREIA teaches of methods for the rapid screening of candidate protein therapeutics. In particular, the instant invention provides compositions and methods for assaying the behavior of candidate protein therapeutics in complex biological fluids and for identifying those candidate protein therapeutics exhibiting desirable pharmacokinetic properties in such fluids (abstract). This seems similar to what is instantly being done.
CORREIA further teaches of using in vitro analytical techniques to provide stability and activity data for the therapeutic or candidate proteins (Page 1, last paragraph, page 2, first paragraph).
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758
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