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 .
Election/Restrictions
Applicant’s election without traverse of Species I (the method wherein the one component is a polypeptide or antibody or antibody fragment) in the reply filed on May 28, 2026 is acknowledged.
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.
Claim(s) 1-9, 12-18 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Linse et al., “Kinetic fingerprints differentiate the mechanisms of action of anti-AB antibodies”, Nature Structural & Molecular Biology, Vol. 27, December 2020. [One author is co-inventor of the present application.]
Applicant’s claim 1 recites the following.
A method of determining the diffusion coefficient of one or more components in a polydisperse sample, the method comprising the steps of:
introducing an auxiliary fluid flow into a fractionation channel; introducing the polydisperse sample comprising one or more components into the fractionation channel;
allowing the sample fluid and the auxiliary fluid to create a combined flow;
fractionating the combined flow into two or more fractions by diffusive sizing;
subsequently separating two or more components from each fraction by creating a distribution of the components within a separation channel;
detecting a characteristic of each of the two or more components in each fraction;
and comparing the characteristic of each component in each fraction in order to determine the diffusion coefficient of each of the one or more components in the polydisperse sample
wherein the method further comprising the step of processing the components in one or more of the fractions to separate and detect solutions added before or during the claimed method.
Linse discloses probing directly the stoichiometry and affinity of the interactions between each antibody and Aβ42 monomers and fibrils (Fig. 3 and Table 1). Monomers and fibrils were selected for studies since oligomers are not amenable to equilibrium binding measurements due to their transient nature. The interactions were investigated by monitoring changes in the diffusion coefficients of the equilibrate species through microfluidic diffusional sizing. The data confirm the low affinity of aducanumab for Aβ42 monomers, and high affinity for fibrils. (Page 1128, left column, last partial para.)
See figure 3 on page 1130 at section “a” which show a “buffer” flow [equivalent to Applicant’s auxiliary fluid flow in a fractionation channel]. Section “a” also shows a “sample” flow [equivalent to applicant’s polydisperse sample comprising one or more components in the fractionation channel]. Section “a” also shows that this sample flow and buffer fluid [auxiliary fluid] are combined into a combined flow.
Page 1130, in the section regarding figure 3, discloses detection being performed at the end of the channel, and diffused fraction of Alexa-647 antibodies.
Linse also discloses that the sample was injected in one half of the channel and at the outlet, the fractional fluorescence intensity in the two halves of the channel were analyzed separately (see section under binding measurements using microfluidic diffusional sizing (MDS), on the second page after page 1133 [no page number given on the page itself]. This meets Applicant’s limitations of separating two or more components from each fraction by creating a distribution of the components within a separation channel after the step of fractionating the combine flow into two or more fractions by diffusive sizing, and before a step of comparing the characteristic of each component in each fraction in order to determine the diffusion coefficient of each of the one or more components.
It is not clear in Linse as to a step of comparing the characteristic of each component in each fraction in order to determine the diffusion coefficient of each of the one or more components in the polydisperse sample. However this step appears to be understood, or alternatively an obvious step in order to perform the disclosed method (see disclosure on page 1128, left column, last partial paragraph, disclosing that the interactions were investigated by monitoring changes in the diffusion coefficients of the equilibrated species through microfluidic diffusional sizing).
As to Applicant’s limitation of “further comprising the step of processing the components in one or more of the fractions to separate and detect solutions added before or during the claimed method”, this broad recitation encompasses any step of processing the components before or after the steps disclosed by Linse mentioned above, such as a step of purification or concentration, as known in the art (see also section under “Purification of Aβ1-42 peptide” one page after page 1133 [no page number is given for this page], or collection of sample at the end of the reaction and/or providing the sample fraction onto polyacrylamide gradient gels, as known in the art (see also section under “SDS-PAGE analysis of monomer concentration at the end of the reaction” one page after page 1133.)
As to claim 2, see disclosure of collection of sample at the end of the reaction and/or providing the sample fraction onto polyacrylamide gradient gel (see section under “SDS-PAGE analysis of monomer concentration at the end of the reaction” one page after page 1133.)
As to claim 3, see under the heading “Purification of Aβ1-42 peptide” one page after page 1133 [no page number is given for this page].
As to claims 4-8, 16, see Linse’s disclosure that the sample was injected in one half of the channel and at the outlet, the fractional fluorescence intensity in the two halves of the channel were analyzed separately (see section under binding measurements using microfluidic diffusional sizing (MDS), on the second page after page 1133 [no page number given on the page itself]. See also page 1130 in the discussion of “Fig. 3” “Binding affinity of the antibodies to Aβ42 monomers and fibrils”, which discloses observation of diffused fraction of fluorescent species at the end of the microfluidic channel.
Claim 9 recites “wherein the processing step comprises the step of adding an additive into each fraction”. This broad limitation encompasses the buffer reagent in the buffer fluid flow shown in Figure 3, section (a) on page 1130.
As to claims 12, 13 and 15, see disclosure of Linse under “SDS-PAGE analysis of monomer concentration at the end of the reaction” one page after page 1133, disclosing analysis using SDS-PAGE on polyacrylamide gradient gels). Regarding claim 13, capillary electrophoresis is well-known in the art, and it would have been obvious or predictable by one skilled in the art that capillary electrophoresis can alternatively be used.
As to claim 14, while Linse is silent as to the two components being in a native state prior to and/or during fractionation of the combined fluid flow, this is understood, or alternatively, it would have been obvious or predictable to one skilled in the art that the technique disclosed by Linse can operate with such components in the same manner.
As to claim 17, Aβ42 monomers and fibrils (Fig. 3 and Table 1; and page 1128, left column, last partial para.) are biomolecules.
As to claims 18 and 21, the Aβ42 monomer is a polypeptide. Regarding claim 21, the term “multi-biomolecule complex” is recited in the alternative (i.e., an alternative to a polypeptide, for instance.)
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Linse et al., “Kinetic fingerprints differentiate the mechanisms of action of anti-AB antibodies”, Nature Structural & Molecular Biology, Vol. 27, December 2020. [One author is co-inventor of the present application]
in view of US 20110081660 (“Orser”).
Linse, discussed above, is silent as to the processing step comprising the step of concentrating the components in each fraction using a pull down assay or immune-precipitation (as recited in Applicant’s claim 10).
Linse is also silent as to the processing step comprising adding a magnetic bead in the pull down assay in which the magnetic bead is functionalized to have a specific affinity to each or a subset of the components in each fraction.
However, this technique is well-known for capturing labeled material and washing to remove unbound label before detection, as demonstrated by Orser (see para. 0092). It would have been obvious to one skilled in the art to utilize magnetic beads in a pull down assay, as is well known in the art and as shown by Orser, for washing to remove unbound label as would be desirable for detection of bound label.
Conclusion
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/Ann Montgomery/Primary Examiner, Art Unit 1678
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