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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Status of Claims
Claims 1-4, 7-13, 16-17, 21-24, 26-35 are pending. Claims 21-24 are withdrawn. Claims 31-35 are new. Claims 5-6, 14-15, 18-20 and 25 are canceled. Claims 1-4, 7-13, 16-17 and 26-35 are under examination.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 7-8, 10-11, 13, 26 and 34-35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Eriksson et al. (“Studies of drug binding to plasma proteins using a variant of equilibrium dialysis”, Journal of Pharmaceutical and Biomedical Analysis 38 (2005) 381–389, 892 dated 01/14/2026).
Eriksson teaches the plasma protein binding of three model compounds was investigated using a variant of equilibrium dialysis, comparative equilibrium dialysis, and the results were compared with those obtained with ultrafiltration (see abstract). Eriksson teaches in comparative equilibrium dialysis, the buffer that the plasma is dialysed against in traditional equilibrium dialysis is replaced by, for example, plasma from other species and the comparative equilibrium dialysis method has the advantage that the unbound concentration (Cu) does not need to be measured, which can be difficult for drugs with extremely small unbound fractions but instead the ratio of the total drug concentration (Ctot) on either side of the dialysis membrane at equilibrium (see abstract). Eriksson teaches two chambers divided by a semipermeable membrane (see pg. 382, left col., para. 1). Eriksson teaches the first model compound having an unbound fraction (Fu) of about 0.05% in human plasma, the time to reach equilibrium is a direct measure of the relative binding properties of the two plasma types and the first model compound having an unbound fraction (Fu) of about 0.05% in human plasma and the second model compound, the more weakly bound drug NAD-299 (with an unbound fraction of about 2% in human plasma), the CED equilibration times were considerably shortened (<16h) (see abstract). NAD-299 structure read on the claimed analyte and claimed molecular weight (see claim 13). Also, Eriksson teaches the claimed biological samples A and B. Thus, NAD-299 would have the claimed ratios. Fig. 1 shows comparative equilibrium dialysis experiments measuring a first set of concentrations of the analyte in bound form and unbound form in the donor solution and the acceptor solution. Figs. 2-3 would read the first set of concentrations are measured two or more times on an every-fixed time basis or an every-key-time basis and calculating the relative Fu ratio. Eriksson teaches the relationship between the unbound and total concentrations in plasma is Ctot = Cu/Fu in formula (1) (see pg. 382, left col., last para.) ang Table 5 teaches ratios of Fu from different samples (pg. 387). Eriksson teaches NAD-299 which was performed under <16 h (see above). Eriksson further teaches that both NAD-299 and tolterodine are mainly bound to α1-AGP (see Table 1).
With respect to claim 2, Eriksson teaches different concentrations were performed through comparative equilibrium dialysis method.
With respect to claim 3, Eriksson teaches the plasmas were diluted with buffer (see pg. 382, left col., middle of para. 1 and Fig. 1).
With respect to claims 7-8, Fig. 1 shows that human plasma and rat plasma.
With respect to claims 10-11, Fig. 1 shows that human plasma and rat plasma, which are mammals.
With respect to claim 13, Eriksson teaches measuring NAD-299 compound which has a MW of 486.5g (see pg. 384, left col., section 2.3).
With respect to claim 26, 1 mL chambers were used and filled with 0.8 mL plasma per chamber (see pg. 383, right col., last para.).
With respect to claims 34-35, Eriksson teaches NAD-299 which was performed under <16 h (see above in claim 1). Eriksson further teaches that both NAD-299 and tolterodine are mainly bound to α1-AGP (see Table 1). NAD-299 structure read on the claimed analyte and claimed molecular weight (see claim 13). Also, Eriksson teaches the claimed biological samples A and B. Thus, NAD-299 would have the claimed ratios.
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.
Claims 4, 9, 12, 16-17 and 31-33 are rejected under 35 U.S.C. 103 as being unpatentable over Eriksson et al. (“Studies of drug binding to plasma proteins using a variant of equilibrium dialysis”, Journal of Pharmaceutical and Biomedical Analysis 38 (2005) 381–389) applied to claim 1 above, and further in view of Kalvass et al. (“Mathematical and Experimental Validation of Flux Dialysis Method: An Improved Approach to Measure Unbound Fraction for Compounds with High Protein Binding and Other Challenging Properties”, Drug Metab Dispos, vol. 46, pgs. 458-469, published April 2018, IDS submitted 06/12/2023, #NPL9).
Eriksson has been discussed above. Eriksson does not explicitly teach the MW cutoff of the semipermeable membrane is 50 kDa or less (claim 4), the biological samples (A) and (B) are serum (claim 9), ClogP of the analyte is 25 or less (claim 12), is a dynamic analysis (claim 16), the claimed expressions (claim 17) and the measurement is performed without necessity or before reaching equilibrium (claims 31-33).
Kalvass teaches a flux dialysis method to measure unbound fraction (fu) of compounds with high protein binding and other challenging properties was tested and validated (see abstract). Kalvass teaches compound initial flux rates of 14 compounds were determined by dialyzing human plasma containing compound (donor side) versus compound-free plasma (receiver side) and measuring the rate of compound appearance into the receiver side (see abstract). Kalvass teaches the dialysis kinetic model (Fig. 1) comprises a donor matrix and a receiver matrix compartment separated by a semipermeable membrane (see pg. 459, right col., last para. of Materials and Methods). Meanwhile, Fig. 1 shows providing a chamber system (I) in which adjacent chambers are separated by a semipermeable membrane permeable to the analyte; adding a donor solution containing a first biological sample (A) and the analyte to one chamber (donor-side chamber) in the chamber system (I); adding an acceptor solution containing a second biological sample (B) to a chamber different from the donor-side chamber (acceptor-side chamber) in the chamber system (I); measuring concentrations of the analyte in the donor solution and the acceptor solution over time (also see caption). Kalvass teaches the model structure was general, allowing consideration of dialysis between any two matrices (e.g., plasma vs. buffer, buffer vs. buffer, plasma vs. plasma (see pg. 459, right col., para. 2 of Materials and Methods). Kalvas teaches the molecular weight cutoff (MWCO) is 12-14 kDa (see pg. 461, left col., para. 2). Kalvass teaches the compound-spiked serum is dialyzed against compound-free serum (see pg. 458, middle of right col.). Kalvass teaches that measuring compound’s fu with the dynamic dialysis method offers advantages over equilibrium dialysis, namely, allowing much higher receiver concentration to be achieved (enabling measurements of lower fu values for a given LLOQ) (see pg. 458, right col., bottom of para. 1). Kalvass teaches the claimed expression 2 (see pg. 459, right col., last para.).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have used the semipermeable membrane as taught by Eriksson with a cutoff molecular weight of 50 kDa or less as taught by Kalvass because it has been recognized by Eriksson and Kalvass to use a semipermeable membrane that has a higher cutoff molecular weight than the analyte and compound for passage of molecules. Additionally, it would have been obvious to have used serum instead of plasma because serum and plasma are derived from blood products and Kalvass teaches that serum can be dialyzed and measured for relative fu values. With respect to dynamic analysis and expressions, it would have been obvious to the person to have performed dynamic analysis and calculated the performance as taught by Kalvass because Kalvass teaches that measured compound’s fu with the dynamic dialysis method offers advantages over equilibrium dialysis, namely, allowing much higher receiver concentration to be achieved by enabling measurements of lower fu values.
The person would have a reasonable expectation of success in performing dynamic analysis from drug binding of Eriksson because it has been well understood by comparative equilibrium dialysis and dynamic analysis to use plasma as samples in chambers.
With respect to claim 12, Eriksson does not teach cLogP. Kalvass teaches cLogP is 0.88 to 8.1 (see pg. 459, left col., middle of para. 5). It would have been obvious to the person to have performed dynamic analysis and calculated the cLogP as taught by Kalvass because Kalvass teaches that measured compound’s fu with the dynamic dialysis method offers advantages over equilibrium dialysis and Eriksson teaches measuring the claimed analyte and biological sample.
With respect to claims 31-33, Eriksson teaches at 22 hr the ratio was about 2, indicating that the system is still far from equilibrium or that the ratio is influenced by other factors (see pg. 386, left col. para. 1). Thus, it would have been obvious to have performed the reaction prior to equilibrium to determine whether the reaction is close to equilibrium state.
Claims 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Eriksson et al. (“Studies of drug binding to plasma proteins using a variant of equilibrium dialysis”, Journal of Pharmaceutical and Biomedical Analysis 38 (2005) 381–389) applied to claim 1 above, and further in view of, as applied to claim 1 above, and further in view of Demarco et al. (WO2017105939A1, published 06/22/2017, 892 dated 01/14/2026).
Eriksson has been discussed above. However, Eriksson does not teach the claimed peptide (see claims 27-30).
Demarco teaches polypeptide modulators of complement activity, including cyclic polypeptide modulators and utilizing such modulators as therapeutics (see abstract). Demarco teaches plasma protein binding was > 99.9 in human, rat and monkey plasma, as determined by equilibrium dialysis at a drug concentration of 10 and 100 µM (see para. [00270]). Demarco teaches a commonly administered medication in paroxysmal nocturnal hemoglobinuria patients is cyclosporine (see para. [00273]).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to have used the equilibrium dialysis as taught by Eriksson with cyclosporine as taught by Demarco and with a reasonable expectation of success because Demarco teaches performing equilibrium dialysis with plasma and drugs at concentration of 10 and 100 µM and cyclosporine is a common medication to administer to patients.
Response to Arguments
Applicant's arguments filed 06/11/2026 have been fully considered but they are not persuasive.
35 U.S.C. 102 rejection:
Applicant argues bottom of page 9 that based on Eriksson, to obtain a relative Fu ratio from the CED method, equilibrium must be reached. When the Ctot measured in Eriksson does not represent the total concentration at equilibrium, the relative Fu ratio is not obtained. Applicant further argues on page 10, para. 1, that Eriksson does not teach that a relative Fu ratio can be obtained for compound 1 with only 22 hours of incubation. Applicant further argues that Eriksson does not teach step 5 of calculating and the analyte has a protein binding ratio of at least 95% for both biological samples.
The arguments are not found persuasive for the following reasons. The claims do not exclude the method without equilibrium and Eriksson’s analytes as NAD-299 and tolterodine (see abstract and Table 1) would read on the structure of the claimed analyte. Also, Eriksson teaches the same claimed biological samples (i.e., A and B having different biological species) and chamber system. As stated in the rejection, the CED equilibration times for NAD-299 were shortened to < 16hrs. If the structures of Eriksson’s analyte, the biological samples (i.e., A and B) and chamber system are the same as claimed, then the protein binding ratio of the analyte would be the same in a reaction. With respect to step 5 of calculating, the tables and figures would read on the claimed invention. Meanwhile, Eriksson was able to determine the unbound fraction Fu ratios (see Table 5), which would read on the phrase calculating, as the claimed calculation is based on the data associated with the concentrations measured in step 4.
35 U.S.C. 103 rejection:
Applicant argues on page 11 that the combination of Eriksson and Kalvass does not teach or suggest the claimed invention. The person would have been taught away from the claimed invention based on Eriksson. Applicant further argues that Eriksson specifically recommends against using CED for measuring relative Fu values. Applicant argues that the claimed invention is directed to measuring relative protein bindings for high protein binding compounds (i.e., protein binding ratios of the analytes are 95% or more). Applicant argues that Kalvass does not cure the deficiencies of Eriksson, as it does not teach or suggest relative Fu ratios which would require different matrix compositions. There is no motivation to modify Eriksson’s CED method of measuring relative Fu ratios based on Kalvass with a reasonable expectation of success. Applicant further argues page 13 that the combination of Eriksson and Demarco also does not teach or suggest the claimed invention, as Demarco does not teach measuring relative Fu values in different biological samples nor resolved the issues identified in Eriksson’s CED method.
The arguments are not found persuasive for the following reasons. As stated above, Eriksson teaches NAD-299 which would read on the claimed analyte and the reaction is with 24-hr. Additionally, it would have been obvious to have combined because it has been recognized by Eriksson and Kalvass to use a semipermeable membrane that has a higher cutoff molecular weight than the analyte and compound for passage of molecules and Kalvass teaches that measured compound’s fu with the dynamic dialysis method offers advantages over equilibrium dialysis, namely, allowing much higher receiver concentration to be achieved by enabling measurements of lower fu values.
Additionally, it would have been obvious to have combined because Demarco teaches performing equilibrium dialysis with plasma and drugs at concentration of 10 and 100 µM and cyclosporine is a common medication to administer to patients. As stated above, Eriksson teaches NAD-299 which would read on the claimed analyte and the reaction is with 24-hr.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/N.P.N/Examiner, Art Unit 1678
/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
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