DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-2, 5-7 and 10-17 are pending in this application.
Applicant’s amendment to the claims filed 09/09/2025 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks filed on 09/09/2025 in response to the non-final rejection mailed on 06/09/2025 is acknowledged and has been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election
The elected subject matter is
Group I, corresponding to claims 1-2, 5 and 16, drawn to a method for coupling an antibody to a surface of a cell,
Species A1) 9N3-SA, and
Species B1) linker-1,
elected with traverse in the reply filed 02/14/2025.
Claims 6-7, 10-15 and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on 02/14/2025.
Claims 1-2, 5 and 16 are being examined on the merits only to the extent they read on the elected subject matter.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 09/22/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Claim Objections
The objection to claim 1 is withdrawn in view of the amendment to recite “obtaining a cell modified with the azide group through a sialic acid metabolic pathway via contacting the sialic acid derivative with the cell such that the cell absorbs the sialic acid derivative, and expressing the azide group on a membrane surface of the cell”.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1-5 and 16 under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention is withdrawn in view of the amendment to cancel claims 3 and 4 and amendment to claim 1 to recite “wherein the conjunction compound bio-orthogonally reacts with the azide group, the conjunction compound is connected to a sulfhydryl group or an amino group of the antibody by a reaction”.
Claim Rejections - 35 USC § 103
Claims 1, 5 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Scripps Research Institute et al. (CN110475566A; cited on the IDS submitted 05/31/2022; reference is made to a machine translation cited on the Form PTO-892 mailed 06/09/2025; herein referred to as Scripps) in view of Han et al. (WO 2019094395 A2; cited on the Form PTO-892 mailed 06/09/2025; herein referred to as Han) and evidentiary references Bardor et al. (J Biol Chem, 2005, 280:4228; cited on the attached Form PTO-892; herein referred to as Bardor) and Jones et al. (Biotechnol Bioeng, 2004, 85:394; cited on the attached Form PTO-892; herein referred to as Jones).
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Claim 1 is drawn to a method for coupling an antibody to a surface of a cell, comprising:
(1) chemically modifying sialic acid to obtain a sialic acid derivative containing an azide group;
(2) obtaining a cell modified with the azide group through a sialic acid metabolic pathway via contacting the sialic acid derivative with the cell such that the cell absorbs the sialic acid derivative, and expressing the azide group on a membrane surface of the cell;
(3) modifying the antibody with a conjunction compound to obtain a modified antibody, wherein the conjunction compound bio-orthogonally reacts with the azide group, the conjunction compound is connected to a sulfhydryl group or an amino group of the antibody by a reaction; and the conjunction compound comprises a compound having any of the structural formulas of linker-1 to linker-5; and
(4) co-culturing the modified antibody with the cell modified with the azide group to enable the conjunction compound of the modified antibody to be connected to the azide group of the cell modified with the azide group by a second reaction.
Scripps relates to engineered cells comprising a chemical or biological moiety covalently bound to a cell surface glycan [abstract], and discusses the need for compositions and methods to label antigen-specific antibodies on the surfaces of natural killer (NK) cells to direct the NKs for targeted treatment of diseased cells [p 2, Background Technique, paras 2 and 4].
Regarding claim 1 and the limitations in step (1), Scripps discloses a method of conjugating CMP-sialic acid to an antibody (CS-IgG) by reacting an antibody bearing a trans-cyclooctene (TCO) moiety with CS-Az-Tz [claim 61], wherein CS-Az-Tz is CMP-sialic acid-azide-tetrazine [p 7, para 6, Fig. 63 description]. Scripps also discloses a method of azide functionalization wherein the protein BSA is reacted with NHS-biotin and NHS-azide, wherein the azide is further reacted with an alkyne by a copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction [Example 7]. Thus one of skill in the art would be able to produce sialic acid derivative containing the azide by using the method of azide functionalization as disclosed by Scripps.
Regarding claim 1 and the limitations in step (2), Scripps discloses an engineered cell comprising a chemical or biological moiety covalently bound to glycans on the cell surface, wherein the chemical or biological moiety is selected from small molecules, polynucleotides, polypeptides and antibodies [claim 1], and that the cell surface glycan is sialic acid [claim 21]. Scripps further discloses an example of in situ one-pot preparation of the cell surface in Figure 1, wherein the azide-containing glycan is added to the cell surface via enzymatic activity [Figure 1, top scheme], as well as a specific example where cells are prepared by incubating CS-IgG and a sialyltransferase enzyme with the cells [claim 61].
Scripps discloses the same general method for use with both fucosyltransferase and sialyltransferase enzymes directed to the modification of fucose and sialyl glycans, respectively, wherein the latter is understood to be a glycan terminated with sialic acid, and discloses that while they used a fucosyltransferase from H. pylori, it is obvious to those skilled in the art that any fucosyltransferase, regardless of origin, can be used for the method [p 10, para 7]. As the sialyltransferase of Scripps is similarly disclosed as either a naturally-occurring or mutant version of sialyltransferase from H. pylori, P. multocida, or P. mermaidi, Scripps discloses that all applications using FucT [the fucosyltransferase] will be similarly implemented by ST [the sialyltransferase] [p 20, Example 47]. In view of the disclosure of Scripps, one of skill in the art would reasonably conclude that any sialyltransferase enzyme can be used to carry out this method as disclosed by Scripps, including a sialyltransferase native to the cell being modified, and therefore the use of said sialyltransferase is interpreted to be encompassed by “a sialic acid metabolic pathway”.
While Scripps teaches the preparation of a cell via transferring a CS-IgG to the surface with an ST enzyme, one of skill in the art would reasonably conclude that the native ST enzymes would be capable of the same activity of transferring a sialic acid to a glycan within the cell, as glycans are understood to be synthesized natively within cells. Furthermore, one of skill in the art would be reasonably expected to conclude that a sialic acid derivative such as the sialic acid azide of Scripps could be absorbed by the cell, as the uptake of sialic acid and derivatives are known to occur through native cellular transport as evidenced by Bardor [abstract] and Jones [p 394, col 2, para 2], and wherein non-natural sialic acid derivatives are known to be taken up by the sialic acid biosynthetic pathway to ultimately be displayed on the surface of cells [Jones, p 394, col 2, para 2]. Therefore one of skill in the art would arrive at this order of method steps through routine optimization of having a cell absorb the sialic acid derivative through the uptake mechanism of the cell’s sialic acid metabolic pathway to be presented outside of the cell for subsequent antibody conjugation to produce the cell of Scripps, as it is common in the art to optimize method steps for to achieved increased efficiency (see MPEP 2144.05.II.A).
Regarding claim 1 and the limitations of step (3), Scripps discloses a method of preparing engineered cells reacting an antibody bearing a TCO moiety with CS-Az-Tz to generate a CMP-sialic acid-antibody conjugate (CS-IgG) [claim 61], wherein CS-Az-Tz is CMP-sialic acid-azide-tetrazine [p 7, para 6, Fig. 63 description], and wherein the TCO moiety is considered to bio-orthogonally react with the azide group based on the reaction scheme shown in [Figure 63C].
Regarding claim 1 and the limitations of step (4), Scripps discloses an example of in situ one-pot preparation of the cell surface in Figure 1, wherein the azide-containing glycan is enzymatically added to the cell surface [Figure 1, top scheme], as well as an example where TCO-IgG antibody conjugates are attached to an azide-containing sialic acid derivative (CS-Az-Tz) [claim 61]. As Scripps also discloses generating engineered cells by incubating cells, sialyltransferase and CS-IgG together [Figure 63D], which is considered to encompass co-culturing of the cell and reagents, one of skill in the art would be able to generate the engineered cell by similarly co-culturing the cell displaying the azide-containing sialic acid with TCO-IgG.
Scripps does not teach the conjugation compound recited in step (3).
Han relates to hydrophilic linkers for antibody drug conjugates [title] and discusses antibody-drug conjugates comprising an antibody conjugated to a biologically active small molecule [para 03] for the target-specific delivery of drugs to cells that include linkers and protein conjugates [abstract].
Regarding claim 1 and the limitation of the conjugation compound comprising linker-1, Han discloses a compound comprising a binding agent (BA), a reactive group (RG1), a spacer (SP1), a linker (LL), and second reactive group (RG2) [claim 6], wherein the binding agent is an antibody with the reactive group and linker shown in the first structure of [claim 31], wherein this structure appears to be the same as the second RG and linker shown in the conjugation compound linker-1 in step (3) of instant claim 1. Han further discloses the reactive groups can be an alkyne and a succinimide, and that in some examples the alkyne reacts with an azide on a modified antibody in [para 85]. Therefore the BA-RG1-SP-L-RG2 construct of Han comprising the antibody, alkyne, spacer, and succinimide are considered to encompass the conjugation compound depicted by linker-1.
In view of Scripps and Han, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Scripps by using the conjugation compound of Han to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the method of Scripps by using the conjugation compound of Han, because Han teaches specific drug-antibody conjugates comprising linkers for the target-specific delivery to cells. One of ordinary skill in the art would have had a reasonable expectation of success because both Scripps and Han discuss antibody conjugates for target-specific delivery in therapeutic applications.
Regarding claims 5 and 16, Scripps discloses compositions and methods to label antigen-specific antibodies on the surfaces of natural killer (NK) cells to direct the NKs for targeted treatment of diseased cells [p 2, Background Technique, paras 2 and 4].
Therefore, the invention of claims 1, 5 and 16 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Scripps and Han as applied to claims 1, 5 and 16 above, and further in view of Xiamen Nuokangde Biological Technology Co Ltd (CN110128490A; cited on the IDS submitted 05/31/2022; reference is made to a machine translation cited on the Form PTO-892 mailed 06/09/2025; herein referred to as Xiamen).
The instant rejection is maintained from the previous Office Action and any newly recited portions are necessitated by claim amendment.
Claim 2 is drawn to the method according to claim 1, wherein the sialic acid derivative containing the azide group comprises a compound having any one of the following structural formulas of 9N3-SA, 5N3-SA, and diN3--SA as depicted in the claim, wherein the 9N3-SA is the elected species currently under examination.
Xiamen relates to carbohydrate derivatives used for surface modification of immune cells [title], and discusses sialic acid derivatives for modifying the surfaces of various immune cells for the treatment of tumors and other diseases [abstract].
Regarding claim 2, Xiamen discloses the production of a sialic acid derivative described in Example 1 involving the mixing of sialic acid, TFA and methanol followed by the addition of sodium azide to produce compound (3) as a pale yellow solid [p 5, middle of page], wherein the scheme is shown on [p 15] of the FOR document, and compound (3) is the 9N3-SA derivative of instant claim 2.
In view of Xiamen, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Scripps and Han by using the sialic acid derivative of Xiamen to arrive at the claimed invention, since the simple substitution of one known element for another results in a predictable result. One of ordinary skill in the art would have recognized that the sialic acid derivative of Scripps and the sialic acid derivative of Xiamen are both azide-containing sialic acid derivatives, and as such both are capable of being incorporated into such methods as described by Scripps. Thus it would have been obvious to one of ordinary skill in the art to replace the sialic acid derivative of Scripps with the sialic acid derivative of Xiamen, as one of ordinary skill in the art would have been able to carry out such a substitution with a reasonable expectation of success because both Scripps and Xiamen discuss the modification of cell surfaces involving sialic acid glycan residues.
Therefore, the invention of claim 2 would have been obvious to one of ordinary skill in the art before the effective filing date.
Response to Remarks: beginning on p. 7 of Applicant’s response to rejections under 35 USC 103; Applicant in summary contends that Scripps is drawn to the formation of GDP-fucose azide instead of a sialic acid derivative containing an azide as recited in the claims; Applicant further contends the CS-IgG molecule of Scripps is generated by reacting a TCO-bearing antibody with the Tz moiety of CS-Az-Tz, and requires a sialyltransferase, and therefore the sialic acid of Scripps does not react with the azide; Applicant further contends claim 1 recites sialic acid combining with azide, the modified sialic acid is absorbed by a cell through a sialic acid metabolic pathway without using sialyltransferase, and the antibody comprising the conjunction compound combines with the cell absorbing the sialic acid modified with the azide group, none of which are disclosed by Scripps.
Applicant’s remarks are considered and found not convincing.
Regarding the assertion that Scripps is drawn to the formation of GDP-fucose azide instead of a sialic acid derivative containing an azide as recited in the claims, the disclosure of Scripps as described above includes a similar general method for use with both fucosyltransferase and sialyltransferase enzymes directed to the modification of fucose and sialyl glycans, respectively, wherein the latter is understood to be a glycan terminated with sialic acid, and discloses that while they used a fucosyltransferase from H. pylori, it is obvious to those of ordinary skill in the art that any fucosyltransferase, regardless of origin, can be used for the method. As the sialyltransferase of Scripps is similarly disclosed as either a naturally-occurring or mutant version of sialyltransferase from H. pylori, P. multocida, or P. mermaidi, Scripps discloses that all applications using FucT [the fucosyltransferase] will be similarly implemented by ST [the sialyltransferase]. In view of the disclosure of Scripps, one of ordinary skill in the art would reasonably conclude that any sialyltransferase enzyme can be used to carry out this method as disclosed by Scripps, including a sialyltransferase native to the cell being modified, and therefore the use of said sialyltransferase is interpreted to be encompassed by “a sialic acid metabolic pathway”, as a sialyltransferase is understood to be part of a sialic acid metabolic pathway.
Regarding the assertion that the CS-IgG molecule of Scripps is generated by reacting a TCO-bearing antibody with the Tz moiety of CS-Az-Tz, and requires a sialyltransferase, and therefore the sialic acid of Scripps does not react with the azide: claim 1 as amended recites a step (1) of chemically modifying sialic acid to obtain a sialic acid derivative containing an azide group, and does not require the reaction of sialic acid directly with an azide. Given a broadest reasonable interpretation, the combination of cited prior art teaches and/or suggests all limitations of the claims.
Regarding the assertion that claim 1 recites the modified sialic acid is absorbed by a cell through a sialic acid metabolic pathway without using sialyltransferase: claim 1 recites a step (2) of obtaining a cell modified with the azide group through a sialic acid metabolic pathway via contacting the sialic acid derivative with the cell such that the cell absorbs the sialic acid derivative, and does not restrict from the use of a sialyltransferase. Given a broadest reasonable interpretation, the combination of cited prior art teaches and/or suggests all limitations of the claims. Furthermore, one of ordinary skill in the art would reasonably conclude that a sialic acid derivative taken up by a cell would be contacted by a sialyltransferase within the cell via the sialic acid metabolic pathway reactions that comprise the formation of glycan and glycoproteins.
Regarding the assertion that claim 1 recites the antibody comprising the conjunction compound combines with the cell absorbing the sialic acid modified with the azide group which is not disclosed by Scripps: Scripps discloses an example of in situ one-pot preparation of the cell surface in Figure 1, wherein the azide-containing glycan is enzymatically added to the cell surface, as well as an example where TCO-IgG antibody conjugates are attached to an azide-containing sialic acid derivative (CS-Az-Tz). As Scripps also discloses generating engineered cells by incubating cells, sialyltransferase and CS-IgG together [Figure 63D], which is considered to encompass co-culturing of the cell and reagents, one of ordinary skill in the art would be able to generate the engineered cell by similarly co-culturing the cell displaying the azide-containing sialic acid with TCO-IgG. As Han discloses the particulars of the conjunction compound recited in the claim, the combined method of Scripps and Han would have been obvious over the claimed method for the reasons set forth in the rejection above.
Conclusion
Status of the Application:
Claims 1-2, 5-7 and 10-17 are pending.
Claims 6-7, 10-15 and 17 are withdrawn.
Claims 1-2, 5 and 16 are rejected.
No claim is in condition for allowance.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH SPANGLER whose telephone number is (571)270-0314. The examiner can normally be reached M-F 7:30 am - 4:30 pm.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656