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 OFFICE ACTION
This Office Action is in response to the papers filed on 15 December 2025.
CLAIMS UNDER EXAMINATION
Claims 1-5, 7-13, 17 and 39-44 have been examined on their merits.
PRIORITY
Provisional Application 62/979,025, filed on 20 February 2020, is acknowledged.
WITHDAWN REJECTIONS
The previous rejections have been withdrawn due to claim amendment.
NEW REJECTIONS
New rejections have been necessitated by claim amendment.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 4-5, 7-13 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Clarke et al. (previously cited; Compositions and Methods For Rapid and Reversible Biomolecular Labeling. US2015/0204857 2015).
Clarke teaches a method of separating a target cell from a sample. The method comprises ([0113] [0154]-[0155]):
(a) incubating the sample with an antibody that binds to the target cell linked to an antibody that binds to a first polymer,
(b) incubating the sample from (a) with a label conjugated to the first polymer,
(c) isolating the target cells bound to the label from the sample,
(d) adding a second polymer to release the target cells bound to the label, and
(e) separating the cells from the label
Clarke teaches “different cells can be isolated based on their unique receptor expression” ([0144]). Clarke teaches a population comprising bright and dim subpopulations which differ in expression of cell surface moiety CD56 (a target moiety) ([0050]). CD56 “dim” cells are interpreted to be a first population comprising lower expression of a target moiety. CD56 “bright” cells are interpreted to read on a second population. CD56+ cells are selected from PBMCs (a sample) using anti-PEG/CD56 tetrameric antibodies and PEG conjugated particles ([0050]). Particles are released using Pluronic F68 (a PEG-based polymer; an enrichment reagent). Clark teaches human CD56+ cells are selected and CD56dim cells are analyzed (Figure 14b). Therefore the first population is isolated from said sample.
Clarke also teaches the following:
The first and second polymer can be the same polymer ([0094]). Clarke teaches regardless of the cell type being isolated, the same polymer-conjugated particles can be released from cells using the same polymer competitor ([0144]). The same polymer can be used for the label passivation, for specific targeting and for specific release ([0146]). The addition of soluble PEG or PEG derivative is “sufficient to quantitatively reverse the interaction” of anti-PEG antibody with PEG in a matter of seconds ([0131]).
It would have been obvious to use soluble PEG to delabel the first population from the particles. One would have been motivated to do so since Clarke teaches either soluble PEG or a PEG-based polymer can be used as a release agent when using an anti-PEG antibody system. See KSRB. One would have had a reasonable expectation of success since Clarke teaches soluble PEG can be used as a release agent to remove particles in the disclosed system. Therefore claim 1 is rendered obvious.
CD56 (supra) is a cell surface marker. Therefore claim 4 is included in this rejection.
CD56 reads on claim 5.
Clarke teaches PEG-conjugated magnetic particles ([0050]). Therefore the art teaches particles that are responsive to a magnetic field. Claim 7 is included in this rejection.
Clarke teaches particles are removed (supra). This is interpreted to read on fractionation. Therefore claim 8 is included in this rejection.
Clarke teaches the most effective regime in which to minimize avidity of the particle-cell interaction is to have a large excess of particles and a limiting (non-saturating) concentration of TAC relative to the cell surface receptors ([0141]). Therefore claim 9 is included in this rejection.
Clarke teaches antibodies ([0119]). Therefore claim 10 is included in this rejection.
A bispecific antibody complex containing both antibodies against the desired cell targets and antibodies against a polymer-conjugated label is used to link the cells and particles together ([0119]). Therefore claim 11 is included in this rejection. The bispecific antibody complex reads on claims 12-13.
Clarke teaches PEG (supra). Claim 17 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claims 2-3 and 39-44 are rejected under 35 U.S.C. 103 as being unpatentable over Clarke et al. in view of Li et al. (Analysis of Competition Binding between Soluble and Membrane-Bound Ligands for Cell Surface Receptors. Biophysical Journal 77(1999) 3395-3406).
Regarding independent claim 2:
The teachings of Clarke as set forth above are reiterated.
The following is also taught:
Clarke teaches “bright” CD56+ cells can be selected ([0056]). Therefore the subpopulation can be isolated from the sample. Clarke teaches the particle can be removed from said cells ([0050]).
Clarke teaches avidity affects the disclosed system. Avidity is the combined strength of multiple binding interactions ([0139]). Clarke teaches label release differs between bright and dim cells ([0050]). Clarke teaches the observation of differences in label release within bright and dim subpopulations of target cells is consistent with the concept of avidity as high-expressing populations will have more ligand-labeled receptors and therefore a higher avidity in the label-cell interaction ([0050]). Low-avidity is observed the target cell has a low-density of ligand labeled receptors ([0045]). Particles are removed from cells by competition ([0069] [0075] [0147]). To remove the particles under physiological conditions, the free soluble second polymer is added to the sample (with a concentration in excess of the polymer-conjugated label) ([0119]). The second polymer is added at a concentration sufficient to release the biological target from the label. The concentration is preferably at least 0.1% w/v ([0091]). Particle release can be optimized ([0141]).
Clarke teaches bright and dim cells release labels differently. The art teaches high expressing populations have higher avidity. Low expressing populations have low avidity. Clarke teaches soluble polymers are used to release labels by competition. The art is silent regarding the use of different concentration of polymer (hence, a different formulation) to release the bright and dim populations.
Li et al. analyze competition between soluble and cell-bound ligands (Abstract).
For a low level of adhesion, or low density of the receptor or ligand, many of the adherent cells must be mediated by just a single bond. A concentration of the soluble competitor that would block half of the receptors would reduce half of the bonds, thereby reducing the number of adherence cells by a half. If the level of adhesion is high, binding is more likely to be mediated by multiple bonds, reducing the number of bonds by a half will weaken many adherent contacts, but less than half of them would dissociate. In other words, to reduce adhesion by a half requires a higher competitor concentration (see page 3404, left column, first paragraph). The art teaches the higher the adhesion (as a result of higher ligand density), the higher the competitor concentration required to achieve the same level of inhibition (page 3400, left column).
It would have been obvious to use a higher concentration of polymer to release labels from the bright cells taught by Clarke. Clarke teaches bright cells release labels differently due to the increased label interactions. One would have been motivated to use a higher competitor concentration to decrease the number of bonds mediating adhesion. One would have had a reasonable expectation of success since Clarke teaches the amount of second polymer used to release the biological target from the particle can be optimized. Therefore claim 2 is rendered obvious.
Clarke teaches CD56+ bright cells are isolated from PBMCs (supra). Therefore claim 3 is included in this rejection.
Clarke teaches PEG (supra). Therefore clam 39 is included in this rejection.
Clarke teaches antibodies ([0119]). Therefore claim 40 is included in this rejection.
A bispecific antibody complex containing both antibodies against the desired cell targets and antibodies against a polymer-conjugated label is used to link the cells and particles together ([0119]). Therefore claim 41 is included in this rejection. The bispecific antibody complex reads on claim 42.
Clarke teaches the second polymer is added the sample at a concentration sufficient to release the biological target from the label ([0098]). The concentration is preferably at least 0.1% w/v. 0.1% w/v overlaps with the claimed range MPEP 2133.03. Therefore claims 43-44 are included in this rejection.
Therefore Applicant’s invention is rendered obvious as claimed.
RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 15 December 2025 are acknowledged. New grounds of rejection have been necessitated by claim amendment.
CONCLUSION
No Claims Are 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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