DETAILED CORRESPONDENCE
Status of the Application
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 17, 2026 has been entered.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-3, 5-7, 9, 10, 13, 14, 19, 21, 22, 24, 25, 34, 36, 37, and 39 are pending in the application.
Applicant’s amendment to the claims, filed July 17, 2026, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks filed July 17, 2026 in response to the final rejection filed May 21, 2026 and the advisory action filed July 9, 2026 are acknowledged and have 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.
Restriction/Election
In response to a requirement for restriction/election filed May 27, 2025, applicant elected without traverse the invention of Group II, pending claims 13, 14, 19, 21, 22, and 39, drawn to the technical feature of a method for covalently modifying a red blood cell, in the reply filed July 17, 2025.
Claims 1-3, 5-7, 9, 10, 24, 25, 34, 36, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Claim Rejections - 35 USC § 112(b)
Claims 13, 14, 19, 21, 22, and 39 are rejected 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 13 (claims 14, 19, 21, 22, and 39 dependent therefrom) recites the broad recitation “the extracellular domain of the at least one endogenous, non-engineered membrane protein of the RBC” in lines 7-8, and the claim also recites “the extracellular domains of endogenous, non-engineered membrane proteins on the surface of a red blood cell” in lines 2-3, which is the narrower statement of the range/limitation. Claim 13 is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Applicant may consider amending the phrase “the extracellular domain of the at least one endogenous, non-engineered membrane protein of the RBC” in lines 7-8 of claim 13 to recite “the extracellular domains of the endogenous, non-engineered membrane proteins on the surface of the RBC.”
Claim Rejections - 35 USC § 103
Claims 13, 14, 19, 21, 22, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Swee et al. (WO 2014/183066 A2; cited on the IDS filed January 6, 2023; hereafter “Swee”) in view of Chen et al. (CN 109797194 A; cited on the IDS filed January 6, 2023; hereafter “Chen”). Reference is made to applicant’s machine translation of Chen (hereafter “Translation”). This rejection has been modified from its previous version in order to address applicant’s amendment to the claims.
As amended, the claims are drawn to a method for covalently modifying a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of the extracellular domains of endogenous, non-engineered membrane proteins on the surface of a red blood cell (RBC), wherein n is 1 or 2, and wherein the method comprises contacting the RBC with a sortase substrate that comprises a sortase recognition motif and an agent, in the presence of a sortase under conditions suitable for the sortase to conjugate the sortase substrate to the glycine(n) and lysine ε-amino group at internal sites of the extracellular domain of the at least one endogenous, non-engineered membrane protein of the RBC by a sortase-mediated reaction, wherein the sortase-mediated reaction comprises a sortase-mediated glycine conjugation and a sortase-mediated lysine side chain ε-amino group conjugation, wherein the sortase is a Staphylococcus aureus transpeptidase A variant comprising the amino acid sequence as set forth in SEQ ID NO: 3, wherein the RBC is a natural RBC that has not been genetically engineered to express a protein comprising a sortase recognition motif or a nucleophilic acceptor sequence.
Regarding instant claim 13, claim 1 of Swee recites a method of conjugating an agent to an animal cell, the method comprising: contacting an animal cell with a sortase substrate that comprises a sortase recognition sequence and an agent in the presence of a sortase under conditions suitable for the sortase to conjugate the sortase substrate to an endogenous, non-engineered polypeptide expressed by the animal cell; and
claim 2 of Swee recites the method of claim 1, wherein the sortase substrate is conjugated to an extracellular portion of an endogenous, non-engineered polypeptide expressed by the cell.
Swee teaches sortase can be used for modification of eukaryotic cell surfaces without requiring that the cells be engineered to express polypeptides comprising a sortase recognition sequence or nucleophilic acceptor sequence, noting that such polypeptides may comprise a sequence of one or more glycines exposed at the cell surface, e.g., in an N-terminal domain, available to act as a nucleophile in a reaction in which sortase is used to conjugate a sortase substrate to the polypeptide (p. 56, paragraph [0066]). Swee teaches the polypeptide modified by the sortase is an integral membrane protein or a peripheral membrane protein (p. 63, paragraph [0088]).
Swee teaches the cells include red blood cells (p. 98, paragraph [0169]) and teaches examples of sortase-mediated conjugation of red blood cells with various agents modified to comprise a sortase recognition sequence (Examples 28-32 beginning at p. 259).
Swee teaches a variant of a naturally occurring sortase may be used (p. 75, paragraph [00118]) and teaches a variant of a wild-type S. aureus sortase comprising P94R/S, D160N, D165A, K190E, and K196T mutations (p. 76, paragraph [00119]).
The differences between Swee and claim 13 are:
Swee does not teach or suggest a Staphylococcus aureus transpeptidase A variant comprising the amino acid sequence of SEQ ID NO: 3; and
Swee does not explicitly teach the sortase substrate is conjugated to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of extracellular domains of endogenous, non-engineered membrane proteins.
Regarding difference 1), Chen teaches S. aureus sortase mutant 1 comprising the mutations P94R/D124G/D160N/D165A/Y187L/E189R/K190E/K196T/F200L (Translation at p. 3, middle) and referred to as “mgSrtA” (Translation at p. 4, fifth full paragraph). Chen teaches mgSrtA can bind a molecule comprising a LPXTG sequence to the cell membrane surface (Translation at p. 4, first paragraph). Chen teaches the surface of the cell membrane has few oligo glycines and mgSrtA exhibits greatly improved efficiency at single glycine residues on the surface of the cell membrane (Translation at p. 5, second paragraph). Chen teaches mgSrtA mutant 1 comprises the mutations P94R/D124G/D160N/D165A/Y187L/E189R/K190E/K196T/F200L (Translation at p. 3, middle) and has the amino acid sequence of SEQ ID NO: 1 (Translation, beginning at p. 7). SEQ ID NO: 1 of Chen is identical to instant SEQ ID NO: 3 (see Appendix at pp. 23-24 of the Office action filed May 21, 2026 for sequence alignment).
In view of the combined teachings of Swee and Chen, it would have been obvious to one of ordinary skill in the art before the effective filing date to use mgSrtA of Chen as the variant sortase in the method of Swee. One would have been motivated and would have expected success because Swee taught the use of a variant sortase comprising the mutations P94R/S, D160N, D165A, K190E, and K196T to conjugate the sortase substrate to a glycine exposed at the cell surface, Chen taught mgSrtA comprising the mutations P94R/S, D160N, D165A, K190E, and K196T, and Chen taught the surface of the cell membrane has few oligo glycines and mgSrtA exhibits greatly improved efficiency at single glycine residues on the surface of the cell membrane.
Regarding difference 2), the combination of Swee and Chen does not teach or suggest the sortase substrate is conjugated to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of extracellular domains of endogenous, non-engineered membrane proteins. However, according to the instant specification, mgSrtA conjugates a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of membrane proteins of RBCs (e.g., paragraph [00155] and Tables 4 and 5). Since inherency may be relied upon in a rejection under 35 U.S.C. 103 (MPEP 2112) and the inherent feature need not be recognized at the relevant time (MPEP 2112.II), it is the examiner’s position that using the mgSrtA of Chen as the variant sortase in the method of Swee would have inherently resulted in conjugating a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of extracellular domains of endogenous, non-engineered membrane proteins of the RBCs.
Regarding instant claim 14, the combination of Swee and Chen does not teach or suggest the sortase substrate is conjugated to a membrane protein recited in claim 14. However, according to the instant specification, mgSrtA conjugates a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of the membrane proteins recited in claim 14 (e.g., Tables 4 and 5) and it is the examiner’s position that using the mgSrtA of Chen as the variant sortase in the method of Swee would have inherently resulted in conjugating a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of membrane proteins recited in claim 14.
Regarding instant claim 19, Swee teaches sortase substrates include a sortase recognition motif at their C-terminus and teaches the exemplary sortase recognition motifs LPXTGG and LPETGG (p. 44, paragraph [0053]).
Regarding instant claim 21, Swee teaches a wide variety of agents may be conjugated (p. 2, paragraph [0007]) and claim 20 of Swee recites the agent comprises an amino acid, a peptide, a protein, a polynucleotide, a carbohydrate, a tag, a metal atom, a chelating agent, a contrast agent, a catalyst, a polymer, a recognition element, a small molecule, a lipid, a label, an epitope, an antigen, a therapeutic agent, a cross-linker, a toxin, a radioisotope, an antibody, an antibody domain, a click chemistry handle, a virus, a cell, or a particle, and Chen teaches a labeling molecule including a small molecule or a biological macromolecule such as biotin, fluorescent dye, enhanced and green fluorescent protein (eGFP) (Translation at p. 4, first full paragraph).
Regarding instant claim 22, Swee teaches the exemplary sortase recognition motifs LPXTGG and LPETGG (p. 44, paragraph [0053]) and shows a representation of a sortase-modified cell (pp. 60-61, paragraph [0080]), which is encompassed by A1-LPXT-P1 in claim 22.
Regarding instant claim 39, Swee teaches the average circulation time or plasma half-life may be increased (pp. 65-66, paragraph [0093]).
Therefore, the invention of claims 13, 14, 19, 21, 22, and 39 would have been obvious to one of ordinary skill in the art before the effective filing date.
RESPONSE TO REMARKS: Applicant argues the motivation and reasonable expectation of success to combine Swee and Chen cannot be based on the inherency of mgSrtA conjugating a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of extracellular domains of endogenous, non-engineered membrane proteins of the RBCs. According to applicant, combining Swee and Chen based on the inherency of mgSrtA conjugating a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of extracellular domains of endogenous, non-engineered membrane proteins of the RBCs can only be derived with the benefit of impermissible hindsight reasoning.
Applicant’s argument is not found persuasive. Motivation and reasonable expectation of success to combine Swee and Chen are not based on the inherency of mgSrtA conjugating a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of extracellular domains of endogenous, non-engineered membrane proteins of the RBCs. Rather, one would have been motivated and expected success to use mgSrtA of Chen as the variant sortase in the method of Swee because Swee taught the use of a variant sortase comprising the mutations P94R/S, D160N, D165A, K190E, and K196T to conjugate the sortase substrate to a glycine exposed at the cell surface, Chen taught mgSrtA comprising the mutations P94R/S, D160N, D165A, K190E, and K196T, and Chen taught the surface of the cell membrane has few oligo glycines and mgSrtA exhibits greatly improved efficiency at single glycine residues on the surface of the cell membrane. Using mgSrtA of Chen as the variant sortase in the method of Swee would have inherently conjugated a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of extracellular domains of endogenous, non-engineered membrane proteins of the RBCs.
Applicant argues that since Swee fails to provide any specific teachings on the reaction conditions and fails to disclose any data demonstrating any actual modification of RBCs by the sortase-mediated conjugation and Chen provides no disclosure on using mgSrtA to conjugate peptides or proteins to a natural RBC, using mgSrtA of Chen as the variant sortase in the method of Swee does not necessarily result in covalent modification of a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of membrane proteins on the surface of a natural RBC.
Applicant’s arguments are not found persuasive. For reasons stated above, it would have been obvious to use mgSrtA of Chen as the variant sortase in the method taught by Swee to covalently modify an N-terminal glycine of a membrane protein on the surface of a natural RBC. Applicant presents no evidence or line of reasoning as to why the reaction conditions for using mgSrtA in the method of Swee to covalently modify an N-terminal glycine of a membrane protein on the surface of a natural RBC would not also inherently covalently modify a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of membrane proteins on the surface of a natural RBC.
Applicant argues the application discloses a comparison of wild-type and mgSrtA labeling of RBCs, which is a comparison with the closest prior art of Swee, and provides evidence demonstrating unexpected results.
Applicant’s arguments and allegation of unexpected results are not found persuasive. The closest prior art of Swee taught using a variant sortase comprising the mutations P94R/S, D160N, D165A, K190E, and K196T to conjugate the sortase substrate (p. 76, paragraph [00119]). Applicant’s alleged unexpected results are not based on a comparison of Swee’s variant sortase comprising the mutations P94R/S, D160N, D165A, K190E, and K196T and mgSrtA labeling of RBCs and thus, applicant’s results are not based on a comparison with the closest prior art as required by MPEP 716.02(e).
Also, applicant takes the position that covalent modification of a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of membrane proteins on the surface of a natural RBC would not necessarily occur under any conditions (instant remarks at p. 11, middle) while applicant’s results were achieved using specific reaction conditions. In this case, the claims are unlimited with respect to reaction conditions and applying applicant’s position (i.e., covalent modification would not necessarily occur under any conditions) to the alleged unexpected results, one of ordinary skill would not expect applicant’s results to extend to all reaction conditions and would conclude that the unexpected results are not commensurate in scope with the claimed invention as required by MPEP 716.02(d).
For these reasons, the claimed invention would have been prima facie obvious to one of ordinary skill in the art and applicant’s results fail to rebut the prima facie case of obviousness.
Claim Rejections - Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 13, 14, 19, 21, 22, and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 7, 10-12, and 18 of co-pending application 18/251,030 (reference application).
Regarding instant claims 13 and 19, claim 1 of the reference application recites a method for covalently modifying at least one membrane protein of a red blood cell (RBC), comprising contacting the RBC with a sortase substrate that comprises a sortase recognition motif and an agent, in the presence of a sortase under conditions suitable for the sortase to conjugate the sortase substrate to the at least one membrane protein of the RBC by a sortase-mediated reaction,
wherein the sortase substrate comprises a structure of A1-Sp-M, in which
A1 represents the agent, Sp represents one or more optional spacers, and M represents the sortase recognition motif comprising an unnatural amino acid located at position 5 from the direction of N-terminal to C-terminal of the sortase recognition motif, wherein the unnatural amino acid is an optionally substituted hydroxyl carboxylic acid having a formulae of CH2OH-(CH2)n-COOH, n being an integer from 0 to 3, preferably n=0;
claim 5 of the reference application recites the method of claim 1, the wherein the at least one membrane protein is at least one endogenous, non-engineered membrane protein and the sortase substrate is conjugated to the at least one endogenous, non-engineered membrane protein of the RBC by a sortase-mediated glycine conjugation and/or a sortase-mediated lysine side chain ε-amino group conjugation, wherein the sortase-mediated glycine conjugation and/or the sortase-mediated lysine side chain ε-amino group conjugation occur at least on glycine(n) and/or lysine ε-amino group at internal sites of the extracellular domain of the at least one endogenous, non-engineered membrane protein, optionally n being 1 or 2;
claim 7 of the reference application recites the method of claim 5, wherein the RBC has not been genetically engineered to express a protein comprising a sortase recognition motif or a nucleophilic acceptor sequence, and preferably the RBC is a natural RBC such as a natural human RBC; and
claim 10 of the reference application recites the method of claim 9, wherein the sortase is a mgSrtA, and wherein the mgSrtA comprises an amino acid sequence having the amino acid sequence as set forth in SEQ ID NO: 3 (SEQ ID NO: 3 of the reference application is identical to instant SEQ ID NO: 3 and comprises the mutations P94R/S, D124G, D160N, D165A, Y187L, E189R, K190E K196T, and F200L relative to instant SEQ ID NO: 1).
Regarding instant claim 14, the claims of the reference application do not recite a membrane protein recited in claim 14. However, according to the instant specification, mgSrtA conjugates a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of the membrane proteins recited in claim 14 (e.g., Tables 4 and 5) and it is the examiner’s position that practicing the method of the claims of the reference application would inherently result in conjugating a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of a membrane protein recited in claim 14.
Regarding instant claim 21, claim 11 of the reference application recites the method of claim 1, wherein the agent comprises a binding agent, a therapeutic agent, or a detection agent.
Regarding instant claim 22, claim 12 of the reference application recites the method of claim 1, wherein the covalently modified at least one membrane protein on the surface of the BRC comprises a structure of A1-L1-P1, in which L1 is linked to a glycine(n) in P1, and/or a structure of A1-L1-P2 in which L1 is linked to the side chain ε-amino group of lysine in P2, wherein n is 1 or 2; A1 represents the agent; L1 is selected from the group consisting of LPXT, LPXA, LPXS, LPXL, LPXV, LGXT, LAXT, LSXT, NPXT, MPXT, IPXT, SPXT, VPXT, and YPXR; P1 and P2 independently represent the at least one membrane protein; and X represents any amino acid.
Regarding instant claim 39, claim 18 of the reference application recites the method of claim 1, wherein the method is for increasing the circulation time or plasma half-life of the agent in a subject, comprising providing the sortase substrate that comprises the sortase recognition motif and the agent, and conjugating the sortase substrate in the presence of a sortase under conditions suitable for the sortase to conjugate the sortase substrate to at least one membrane protein of the red blood cell by a sortase-mediated reaction.
Therefore, claims 13, 14, 19, 21, 22, and 39 of this application are unpatentable over claims 1, 5, 7, 10-12, and 18 of the reference application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 13, 14, 19, 21, 22, and 39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 18 of co-pending application 18/264,098 (reference application) in view of Swee and Chen. This provisional rejection has been modified from its previous version in order to address applicant’s amendment to the claims.
Regarding instant claim 13, claim 18 of the reference application recites a method for preparing the red blood cell of claim 1, comprising contacting a red blood cell (RBC) with a sortase substrate that comprises a sortase recognition motif and an agent, in the presence of a sortase under conditions suitable for the sortase to conjugate the sortase substrate to the at least one endogenous, non-engineered membrane protein of the RBC by a sortase-mediated reaction, optionally by a sortase-mediated glycine conjugation and/or a sortase-mediated lysine side chain ε-amino group conjugation, wherein the agent comprises a uric acid degrading polypeptide,
wherein the sortase substrate comprises a structure of (A1-Sp)m-M, in which A1 represents an agent, Sp represents the optional spacer, and M represents a sortase recognition motif; m being an integer greater than or equal to 1, optionally m=1 to 3, wherein M is LPET*G with * being 2-hydroxyacetic acid.
The differences between claim 18 of the reference application and claim 13 of this application are:
claim 18 does not recite the sortase is a Staphylococcus aureus transpeptidase A variant comprising the amino acid sequence of SEQ ID NO: 3;
claim 18 does not recite the sortase substrate is conjugated to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of extracellular domains of endogenous, non-engineered surface membrane proteins; and
claim 18 does not recite the RBC is a natural RBC that has not been genetically engineered to express a protein comprising a sortase recognition motif or a nucleophilic acceptor sequence.
Regarding difference 1), Chen teaches S. aureus sortase mutant 1 comprising the mutations P94R/D124G/D160N/D165A/Y187L/E189R/K190E/K196T/F200L (Translation at p. 3, middle) and referred to as “mgSrtA” (Translation at p. 4, fifth full paragraph). Chen teaches mgSrtA can bind a molecule comprising a LPXTG sequence to the cell membrane surface (Translation at p. 4, first paragraph). Chen teaches the surface of the cell membrane has few oligo glycines and mgSrtA exhibits greatly improved efficiency at single glycine residues on the surface of the cell membrane (Translation at p. 5, second paragraph).
In view of the teachings of Chen, it would have been obvious to one of ordinary skill in the art to use mgSrtA of Chen as the sortase in the method of claim 18 of the reference application. One would have been motivated and would have expected success to use mgSrtA of Chen as the sortase in the method of claim 18 of the reference application because the method of claim 18 of the reference application includes a sortase-mediated glycine conjugation, and Chen taught mgSrtA with greatly improved efficiency at single glycine residues on the surface of the cell membrane.
Regarding difference 2), Swee teaches sortase can be used for modification of eukaryotic cell surfaces without requiring that the cells be engineered to express polypeptides comprising a sortase recognition sequence or nucleophilic acceptor sequence, noting that such polypeptides may comprise a sequence of one or more glycines exposed at the cell surface, available to act as a nucleophile in a reaction in which sortase is used to conjugate a sortase substrate to the polypeptide (p. 56, paragraph [0066]).
In view of the teachings of Swee, it would have been obvious to one of ordinary skill in the art for the at least one endogenous, non-engineered membrane protein of the RBC to comprise a sequence of one or more glycines exposed at the cell surface. One would have been motivated and would have expected the at least one endogenous, non-engineered membrane protein of the RBC to comprise a sequence of one or more glycines exposed at the cell surface because Swee taught polypeptides modified by sortase may comprise a sequence of one or more glycines exposed at the cell surface.
While Swee does not teach the sortase substrate is conjugated to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of extracellular domains of endogenous, non-engineered surface membrane proteins, according to the instant specification, mgSrtA conjugates a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of the membrane proteins recited in claim 14 (e.g., Tables 4 and 5) and it is the examiner’s position that using the mgSrtA of Chen as the sortase in the method of claim 18 of the reference application would inherently result in conjugating a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of membrane proteins of the RBC.
Regarding difference 3), Swee teaches the cell surfaces can be modified without requiring that the cells be engineered to express polypeptides comprising a sortase recognition sequence or nucleophilic acceptor sequence (p. 56, paragraph [0066]).
In view of the teachings of Swee, it would have been obvious to one of ordinary skill in the art for the RBC to be a natural RBC that has not been genetically engineered to express a protein comprising a sortase recognition motif or a nucleophilic acceptor sequence. One would have been motivated and would have expected for the RBC to be a natural RBC that has not been genetically engineered to express a protein comprising a sortase recognition motif or a nucleophilic acceptor sequence because Swee teaches the cell surfaces can be modified without requiring that the cells be engineered to express polypeptides comprising a sortase recognition sequence or nucleophilic acceptor sequence.
Regarding instant claim 14, the claims of the reference application do not recite a membrane protein recited in claim 14. However, according to the instant specification, mgSrtA conjugates a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of the membrane proteins recited in claim 14 (e.g., Tables 4 and 5) and it is the examiner’s position that using the mgSrtA of Chen as the sortase in the method of claim 18 of the reference application would inherently result in conjugating a sortase substrate to a non-N-terminal glycine(n) and a lysine ε-amino group at internal sites of membrane proteins recited in claim 14.
Regarding instant claim 19, Swee teaches sortase substrates include a sortase recognition motif at their C-terminus and teaches the exemplary sortase recognition motifs LPXTGG and LPETGG (p. 44, paragraph [0053]).
Regarding instant claim 21, claim 18 of the reference application recites the agent comprises a uric acid degrading polypeptide. Also, Swee teaches a wide variety of agents may be conjugated (p. 2, paragraph [0007]) and claim 20 of Swee recites the agent comprises an amino acid, a peptide, a protein, a polynucleotide, a carbohydrate, a tag, a metal atom, a chelating agent, a contrast agent, a catalyst, a polymer, a recognition element, a small molecule, a lipid, a label, an epitope, an antigen, a therapeutic agent, a cross-linker, a toxin, a radioisotope, an antibody, an antibody domain, a click chemistry handle, a virus, a cell, or a particle, and Chen teaches a labeling molecule including a small molecule or a biological macromolecule such as biotin, fluorescent dye, enhanced and green fluorescent protein (eGFP) (Translation at p. 4, first full paragraph).
Regarding instant claim 22, Swee teaches the exemplary sortase recognition motifs LPXTGG and LPETGG (p. 44, paragraph [0053]) and shows a representation of a sortase-modified cell (pp. 60-61, paragraph [0080]), which is encompassed by claim 22.
Regarding instant claim 39, Swee teaches the average circulation time or plasma half-life may be increased (pp. 65-66, paragraph [0093]).
Therefore, claims 13, 14, 19, 21, 22, and 39 of this application are unpatentable over claim 18 of the reference application in view of Swee and Chen. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
RESPONSE TO REMARKS: Applicant argues the instant application has an earlier patent term filing date than those of the reference applications and the provisional rejections should be withdrawn in accordance with MPEP 1490(VI)(D)(2)(a) and MPEP 804.I.B.1.(b).(i).
Applicant’s arguments are not found persuasive because the provisional rejections are not the only remaining rejections in this application.
Conclusion
Status of the claims:
Claims 1-3, 5-7, 9, 10, 13, 14, 19, 21, 22, 24, 25, 34, 36, 37, and 39 are pending.
Claims 1-3, 5-7, 9, 10, 24, 25, 34, 36, and 37 are withdrawn from consideration.
Claims 13, 14, 19, 21, 22, and 39 are rejected.
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID J STEADMAN whose telephone number is (571)272-0942. The examiner can normally be reached Monday to Friday, 7:30 AM to 4:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MANJUNATH N RAO can be reached on 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/David Steadman/Primary Examiner, Art Unit 1656
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