Office Action 2: Notice of Allowance (2025-01-16)

CLAIMS:
Amendments to the Claims

1\. - 59. (Canceled)258

60\. (Currently Amended) A method of forcing programmed cell death protein ligand-1 (PD-L1), expressed on the surface of a breast cancer cell, to degrade in a lysosome, comprising the step of physically linking PD-L1 to prolactin receptor (PRLR) by contacting the breast cancer cell with an antibody that comprises (a) an antigen-binding fragment of an anti-PD-L1 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody,
wherein the antibody binds to PD-L1 and PRLR on the same breast cancer cells\[\[;\]\] wherein PD-L1 is transported to a lysosome through its physical linkage to PRLR and degraded=\[\[;\]\] and wherein the lysosomal degradation of PD-L1 through its physical linkage to PRLR is greater than the lysosomal degradation of PD-L1 not physically linked to PRLR.

61\. (Previously Presented) The method of claim 60, wherein the antibody is a bispecific antibody.

62\. (Previously Presented) The method of claim 60, wherein the breast cancer cell is in vivo.

63\. (Previously Presented) The method of claim 61, wherein the bispecific antibody is an anti-PD-L1 x anti-PRLR bispecific antibody.

64\. (Currently Amended) A method of killing a breast cancer cell that expresses on its surface a PD-L1 molecule and a PRLR destroyer molecule, the method comprising the steps of:
(i) contacting the breast cancer cell with an anti-PD-L1 bivalent monospecific antibody conjugated to a cytotoxic agent;\[\[,\]\] and

(ii) physically linking PD-L1 to PRLR on the breast cancer cell of part (i) by contacting the cell with an antibody that comprises (a) an antigen-binding fragment of an anti- PD-L1 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody for simultaneous binding to PD-L1 and PRLR on the same cell,
wherein the PD-L1 molecule and the cytotoxic agent are subsequently transported to a lysosome within the breast cancer cell through the physical linkage between the PD-L1 molecule and the PRLR destroyer molecule.

65\. (Previously Presented) The method of claim 64, wherein the cytotoxic agent is a radioisotope, a toxin, or a drug.

66\. (Currently Amended) The method of claim 65, wherein the toxin is a calicheamicin, an auristatinl or a maytansine-based cytotoxin.

67\. (Previously Presented) The method of claim 64, wherein the breast cancer cell is a T47D cell.

68\. (Previously Presented) The method of claim 64, wherein the breast cancer cell is in vivo.

69\. (Previously Presented) The method of claim 64, wherein cell-killing potency of the cytotoxic agent is enhanced by the presence of the antibody.

70\. (Previously Presented) The method of claim 64, wherein the antibody that physically links PD-L1 with PRLR is a bispecific antibody.

71\. (Previously Presented) A method of inhibiting the growth or promoting the regression of a tumor that comprises a breast cancer cell that expresses on its surface both a PD-L1 molecule and a PRLR destroyer molecule, the method comprising killing the breast cancer cell according to the method of claim 64.

72\. (Previously Presented) The method of claim 71, wherein the antibody that physically links PD-L1 with PRLR is an anti-PD-L1 x anti-PRLR bispecific antibody.

73\. (Previously Presented) The method of claim 71, wherein the cytotoxic agent is a maytansinoid-based cytotoxin.

74\. (Previously Presented) A method of killing a breast cancer cell that expresses on its surface a PD-L1 molecule and a PRLR destroyer molecule, the method comprising the step of physically linking PD-L1 to PRLR by contacting the cell with an antibody cytotoxic agent conjugate that comprises (a) an antigen-binding fragment of an anti-PD-L1 antibody, (b) an antigen-binding fragment of an anti-PRLR antibody, and (c) a cytotoxic agent,
wherein the PD-L1 molecule and the cytotoxic agent, through the physical linkage between the PD-L1 molecule and the PRLR destroyer molecule, are subsequently transported to a lysosome within the breast cancer cell.

75\. (Previously Presented) The method of claim 74, wherein the cytotoxic agent is a radioisotope, a toxin, or a drug.

76\. (Previously Presented) The method of claim 75, wherein the toxin is a calicheamicin, an auristatin, or a maytansine-based cytotoxin.

77\. (Previously Presented) The method of claim 74, wherein the breast cancer cell is a T47D cell.

78\. (Previously Presented) The method of claim 74, wherein the breast cancer cell is in vivo.

79\. (Previously Presented) The method of claim 74, wherein cell-killing potency of the cytotoxic agent is enhanced by the presence of the antibody.

80\. (Previously Presented) The method of claim 74, wherein the antibody cytotoxic agent conjugate comprises an anti-PD-L1 x anti-PRLR bispecific antibody.

81\. (Previously Presented) A method of inhibiting the growth or promoting the regression of a tumor that comprises a breast cancer cell that expresses on its surface both a PD-L1 molecule and a PRLR destroyer molecule, the method comprising killing the breast cancer cell according to the method of claim 74.

82\. (Previously Presented) The method of claim 81, wherein the cytotoxic agent is a maytansinoid-based cytotoxin.

83\. (Previously Presented) The method of claim 81, wherein the antibody cytotoxic agent conjugate comprises an anti-PD-L1 x anti-PRLR bispecific antibody.

84\. (Currently Amended) A method of forcing PD-L1, expressed on the surface of a breast cancer cell, to degrade in a lysosome, comprising the step of physically linking PD-L1 to PRLR by contacting the breast cancer cell with an antibody that comprises (a) an antigen-binding fragment of an anti-PD-L1 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody,
wherein the antibody binds to PD-L1 and PRLR on the same breast cancer cells\[\[;\]\] wherein PD-L1 is transported to a lysosome through its physical linkage to PRLR and degraded=\[\[;\]\] and wherein,in the presence of an inhibitor of protein synthesis, at least 40% of PD-L1 in the breast cancer cell is degraded after about 2 hours of contacting the breast cancer cell with the antibody=\[\[;\]\] and/or

in the presence of an inhibitor of protein synthesis, at least 80% of PD-L1 in the breast cancer cell is degraded after about 4 hours of contacting the breast cancer cell with the antibody.

85\. (Previously Presented) The method of claim 84, wherein the antibody is a bispecific antibody.

86\. (Previously Presented) The method of claim 85, wherein the bispecific antibody is an anti-PD-L1 x anti-PRLR bispecific antibody.

87\. (Currently Amended) A method of forcing PD-L1, expressed on the surface of a breast cancer cell, to degrade in a lysosome, comprising the step of physically linking PD-L1 to PRLR by contacting the breast cancer cell with an antibody that comprises (a) an antigen-binding fragment of an anti-PD-L1 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody,
wherein the antibody binds to PD-L1 and PRLR on the same breast cancer cells\[\[;\]\] wherein PD-L1 is transported to a lysosome through its physical linkage to PRLR and degraded=\[\[;\]\] and wherein degradation of PD-L1 is dependent on the dose of the antibody.

88\. (Previously Presented) The method of claim 87, wherein the antibody is a bispecific antibody.

89\. (Previously Presented) The method of claim 88, wherein the bispecific antibody is an anti-PD-L1 x anti-PRLR bispecific antibody.

OFFICE ACTION:
Reasons for Allowance
The following is an examiner’s statement of reasons for allowance: Cygnar et al (WO2013/138400, reference of the IDS filed 9/23/2021) teach therapeutic methods comprising (a) a toxin- or drug-conjugated antigen-binding molecule that specifically binds a tumor-associated antigen; and (b) a multi-specific antigen-binding molecule comprising (i) a first binding domain that specifically binds an internalizing effector protein  and (ii) a second binding domain that specifically binds the toxin- or drug-conjugated antigen-binding molecule. In this embodiment, the multi-specific antigen-binding molecule functions to link the toxin- or drug-conjugated antigen-binding molecule to the internalizing effector protein, which thereby functions to physically link the tumor associated antigen to the internalizing effector protein.  Cygnar et al teach that internalization of the toxin-labeled anti-tumor-associated antigen antibody via its connection to the internalizing effector protein would consequently result in targeted tumor cell killing (paragraph [0061]).
Cygnar et al teach that the simultaneous binding of a multi-specific antigen-binding molecule to an internalizing effector protein and a tumor-associated antigen will result in preferential internalization of the multi-specific antigen-binding molecule into tumor cells. Cygnar et al teach that if the multi-specific antigen-binding molecule is conjugated to a drug, toxin or radioisotope or if the multi-specific antigen-binding molecule is administered in combination with an accomplice antibody that is conjugated to a drug, toxin or radioisotope, the targeted internalization of the tumor-associated antigen into the tumor cell via its linkage to the multi-specific antigen-binding molecule, will result in extremely specific tumor cell killing (paragraph [0064]).
Cygnar et al teach that cell surface expressed target proteins include tumor associated antigens such as AFP, ALK, BAGE proteins, β-catenin, brc-abl, BRCA1 , BORIS, CA9, carbonic anhydrase IX, caspase-8, CD40, CDK4, CEA, CTLA4, cyclin-B1 , CYP1 B1 , EGFR, EGFRvll l, ErbB2/Her2, ErbB3, ErbB4, ETV6-AML, EphA2, Fra-1 , FOLR1 , GAGE proteins, GD2, GD3, GloboH, glypican-3, GM3, gp100, Her2, HLA/B-raf, HLA/k-ras, HLA MAGE-A3, hTERT, LMP2, MAGE, MART-1 , mesothelin, ML-IAP, Mud , Mud 6 (), MU M1 , NA17, NY-BR1 , NY-BR62, NY-BR85, NY-ES01, OX40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PLAC1 , PRLR, PRAME, PSMA, RAGE proteins, Ras, RGS5, Rho, SART-1, SART-3, Steap-1 , Steap-2, survivin, TAG-72, TGF-β, TMPRSS2, Tn, TRP-1 , TRP-2, tyrosinase, and uroplakin-3. (paragraph [0059]).  Although Cygnar et al teach PRLR as a cell surface expressed tumor associated antigen, Cygnar et al do not teach PRLR as an internalizing effector protein.
Piccirilli et al (WO2008/014404, reference of the IDS filed 9/23/2021) teach a method of delivering an agent to a cell comprising a prolactin receptor, the method comprising contacting the cell with a complex comprising the agent coupled to a prolactin receptor ligand wherein the agent is, in part, a cytotoxic moiety (claims 1 and 2 of ‘404).  Piccirilli et al do not teach that part of the external domain of a non-prolactin receptor such as PD-L1 on the same cell as the PRLR can be delivered to the cell via the prolactin receptor endocytic pathway.  Piccirilli et al do not teach that the cargo internalized by the prolactin receptor is directed toward the lysosomal pathway in the cell.
Varghese et al (Molecular and Cellular Biology, 2008, Vol. 28, pp. 5275-5287, reference of the IDS filed 9/23/2021) teach that the data regarding lysosomal versus proteasomal pathways for the degradation of PRLR is controversial (page 5278, first column, lines 1-4 under “Results”).  Varghese et al that prolactin binding to PRLR stimulates PRLR ubiquitination and leads to PRLR internalization, sorting to the lysosomes and lysosomal degradation (page 5276, first column, lines 1-3 of the second full paragraph).  Varghese et al are silent regarding cargo bound to the internalized PRLR with respect to sorting the cargo-bound PRLR into the lysosomes for lysosomal degradation versus proteasomal degradation.
Thus, the prior art does not teach or suggest that PD-L1, or PD-L1 bound to a cytotoxic cargo can be transported and degraded in a lysosome through physical linkage of  the PD-L1 receptor to PRLR.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”

APPLICANT REBUTTAL: REMARKS/ARGUMENTS
Specification
The Examiner noted that the specification was previously amended on 11/22/2021 to state that this application is a divisional application of U.S. Patent Application No. 15/202,822 ("the '822 application"), but the species election requirement in the '822 application was withdrawn in the Office Action of 10/19/2018. Thus, the Examiner required correction of the present application to appropriately reflect its relationship to the '822 application as a continuation. This correction is made above. Also filed herewith are (i) a supplemental Application Data Sheet correcting the relationship to the '822 application and (ii) a Request for Corrected Filing Receipt. Accordingly, Applicant respectfully requests that the Examiner withdraw this objection.
Status of the Claims
Claims 60-89 are pending and under examination in this application, claims 1-59 having been previously canceled.
Claims 60, 64, 66, 84, and 87 are amended to correct minor clerical errors. No substantive amendments are made to the claims, and no new matter is added.
Lack of comment on any of the Examiner's remarks should not be construed as
agreement herewith. Reconsideration of the application is respectfully requested in view of the following remarks.
Nonstatutory Double Patenting
Claims 60-89 were rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over claims 1-30 of U.S. Patent No. 11,129,903 in view of Hasan et al. (2011) Expert Opinion on Therapeutic Targets 15:1211-1225 (Hasan). Solely to expedite prosecution and without acquiescing with respect to any ground of rejection, an electronic terminal disclaimer over U.S. Patent No. 11,129,903 is filed concurrently herewith. Accordingly, Applicant respectfully requests withdrawal of this nonstatutory double patenting rejection.
Claims 60-83 were also rejected on the ground of nonstatutory double patenting as
allegedly being unpatentable over claims 1-29 of U.S. Patent No. 11,191,844 in view of Hasan.
Solely to expedite prosecution and without acquiescing with respect to any ground of rejection, an electronic terminal disclaimer over U.S. Patent No. 11,191,844 is filed concurrently herewith. Accordingly, Applicant respectfully requests withdrawal of this nonstatutory double patenting rejection.
It is not believed that extensions of time or fees for net addition of claims are required, beyond those that may otherwise be provided for in documents accompanying this paper. However, in the event that additional extensions of time are necessary to allow consideration of this paper, such extensions are hereby petitioned under 37 CFR § 1.136(a), and any fee required therefor (including fees for net addition of claims) is hereby authorized to be charged to Deposit Account No. 16-0605.
Respectfully submitted, /Stephen H. Schilling/Stephen H. SchillingRegistration No. 67,258


CITED REFERENCE SUMMARIES: Ref WO2013138400: Claims:
A multispecific antigen-binding molecule comprising: a first antigen-binding domain (D1 ); and a second antigen-binding domain (D2); wherein D1 specifically binds a target molecule (T); and wherein D2 specifically binds an internalizing effector protein (E); wherein the simultaneous binding of T and E by the multispecific antigen-binding molecule attenuates the activity of T to a greater extent than the binding of T by D1 alone.
The multispecific antigen-binding molecule of claim 1 , wherein E is a cell surface- expressed molecule that is directly internalized into the cell.
The multispecific antigen-binding molecule of claim 2, wherein E is selected from the group consisting of CD63, MHC-I, Kremen-1 , Kremen-2, LRP5, LRP6, transferrin receptor, LDLr, MAL, V-ATPase, and ASGR.
The multispecific antigen-binding molecule of claim 2, wherein D2 comprises a ligand, or portion of a ligand, that specifically binds E.
The multispecific antigen-binding molecule of claim 1 , wherein E is a soluble ligand that is internalized into a cell via the interaction between E and an internalizing cell surface- expressed receptor molecule.
The multispecific antigen-binding molecule of claim 5, wherein E is transferrin or a portion thereof that is capable of binding to membrane-expressed transferrin receptor.
The multispecific antigen-binding molecule of claim 5, wherein D2 comprises a receptor, or ligand-binding portion of a receptor, that specifically binds E.
The multispecific antigen-binding molecule of claim 1 , wherein T is a cell surface- expressed target molecule.
The multispecific antigen-binding molecule of claim 8, wherein T is selected from the group consisting of IL-4R, IL-6R, PRLR, NavU, GCGR, and HLA-B27.
The multispecific antigen-binding molecule of claim 8, wherein D1 comprises a ligand, or portion of a ligand, that specifically binds T.
The multispecific antigen-binding molecule of claim 1 , wherein T is an intracellular precursor of a secreted or transmembrane protein.
The multispecific antigen-binding molecule of claim 1 , wherein T is a soluble target molecule.
The multispecific antigen-binding molecule of claim 12, wherein T is selected from the group consisting of IL-4, IL-6, IL-13, SOST, and DKK1.
The multispecific antigen-binding molecule of claim 12, wherein D1 comprises a receptor, or ligand-binding portion of a receptor, that specifically binds T.
The multispecific antigen-binding molecule of claim 1 , wherein D1 and/or D2 exhibits pH-dependent binding to its antigen.
The multispecific antigen-binding molecule of claim 15, wherein D1 binds T with lower affinity at acidic pH as compared to neutral pH; and/or wherein D2 binds E with lower affinity at acidic pH as compared to neutral pH.
The multispecific antigen-binding molecule of claim 1 , wherein D1 and/or D2 comprise(s) at least one antibody variable region.
The multispecific antigen-binding molecule of claim 17, wherein D1 and/or D2 comprise(s) a heavy chain variable region (HCVR) and a light chain variable region (LCVR).
The multispecific antigen-binding molecule of claim 18, wherein the multispecific antigen-binding molecule is a bispecific antibody.
The multispecific antigen-binding molecule of claim 1 , wherein D1 is derived from an antigen-binding molecule that binds but does not substantially inactivate T on its own.
A method for inactivating or attenuating the activity of a target molecule (T), the method comprising contacting T and an internalizing effector protein (E) with a multispecific antigen-binding molecule, wherein the multispecific antigen-binding molecule comprises a first antigen-binding domain (D1 ) and a second antigen-binding domain (D2), wherein D1 specifically binds T, and wherein D2 specifically binds E; and wherein the simultaneous binding of T and E by the multispecific antigen-binding molecule causes inactivation of T to a greater extent than the binding of T by D1 alone.
The method of claim 21 , wherein E is a cell surface-expressed molecule that is directly internalized into the cell.
The method of claim 21 , wherein E is a soluble ligand that is internalized into a cell via the interaction between E and an internalizing cell surface-expressed receptor molecule.
The method of claim 21 , wherein T is a cell surface-expressed target molecule.
The method of claim 21 , wherein T is a soluble target molecule.
The multispecific antigen-binding molecule of claim 1 , wherein D2 comprises an antigen-binding portion of an anti-CD63 antibody.
The multispecific antigen-binding molecule of claim 26, wherein D1 comprises an antigen-binding portion of an anti-IL-4R antibody.
The multispecific antigen-binding molecule of claim 26, wherein D1 comprises an antigen-binding portion of an anti-SOST antibody.
A multispecific antigen-binding molecule comprising: a first antigen-binding domain (D1 ); and a second antigen-binding domain (D2); wherein D1 specifically binds a target molecule (T); and wherein D2 binds an internalizing effector protein (E); wherein T is a tumor-associated antigen; and wherein the simultaneous binding of T and E by the multispecific antigen-binding molecule causes internalization of the multispecific antigen-binding molecule into a tumor cell.
The multispecific antigen-binding molecule of claim 29, wherein the multispecific antigen-binding molecule is conjugated to a drug, toxin or radioisotope.
The multispecific antigen-binding molecule of claim 29, wherein D2 binds E with low affinity.
A method of targeting a tumor in a subject, the method comprising administering to the subject the multispecific antigen-binding molecule of claim 29, and a second antigen-binding protein that specifically binds T at an epitope that is non-overlapping with the epitope to which D1 binds.
The method of claim 32, wherein the second antigen-binding protein is conjugated to a drug, toxin or radioisotope.
Ref WO2008014404: Claims:
1. A method of delivering an agent to a cell comprising a prolactin receptor comprising: contacting the cell with a complex comprising the agent coupled to a prolactin receptor ligand.
2. The method of claim 1 , wherein the agent is an RNAi-inducing agent, a polynucleotide sequence encoding a polypeptide, an miRNA, an antagomir, a cytotoxic moiety, a chemotherapeutic moiety, a radioactive moiety, an imaging moiety or a nanoparticle.
3. The method of claim 1 or 2 wherein the complex is a fusion polypeptide comprising the agent and the prolactin receptor ligand.
4. The method of the claim 3 wherein the agent is a cytotoxic moiety.
5. The method of claim 4 wherein the cytotoxic moiety is restrictocin.
6. The method of any of claims 1 to 5, wherein the cell is a cancer cell.
7. The method of claim 7, wherein the cancer cell overexpresses the prolactin receptor.
8. The method of any of claims 1 to 7, wherein the cell is an ovarian cancer cell, a breast cancer cell or a prostate cancer cell.
9. The method of any of claims 1 to 8, wherein the prolactin receptor ligand is human placental lactogen.
10. The method of any of claims 1 to 8, wherein the prolactin receptor ligand is human growth hormone.
11. The method of claim 1 , wherein the agent is an RNAi-inducing agent.
12. The method of claimi 1 , wherein the RNAi-inducing agent is an siRNA.
13. A method of inhibiting expression of an mRNA in a cell comprising a prolactin receptor, comprising contacting the cell with a complex comprising an RNAi-inducing agent coupled to a prolactin receptor ligand, wherein the RNAi-inducing agent is complementary to at least a portion of the mRNA.
14. The method of claim 13, wherein the cell overexpresses the prolactin receptor.
15. The method of claim 13 or claim 14, wherein the RNAi-inducing agent is an siRNA.
16. The method of any of claims 13 to 15, wherein the mRNA encodes a cell surface receptor.
17. The method of claim 16, wherein the cell surface receptor comprises c-Met, a member of the EGF receptor family, PDGFR, VEGFR, or a transferrin receptor.
18. The method of any of claims 13 to 15, wherein the mRNA encodes a protease.
19. The method of claim 18, wherein the protease comprises urokinase or a member of the matrix-metalloproteinase family.
20. The method of any of claims 13 to 15, wherein the mRNA encodes a signal transduction molecule.
21. The method of claim 20, wherein the signal transduction molecule comprises Stat-3, Stat-5, Erk1 , Erk2, Jnk1 , Jnk2, p38, Erk5, Akt, c-Kit, a PI3 kinase subunit or ATM.
22. The method of any of claims 13 to 15, wherein the mRNA encodes a transcription factor.
23. The method of claim 22, wherein the transcription factor comprises HIF-1 , HIF-2, c- Jun, JunD, mutant p53 or estrogen receptor.
24. The method of any of claims 13 to 15, wherein the mRNA encodes a cell cycle regulator.
25. The method of claim 24, wherein the cell cycle regulator comprises cyclin D1 , cyclin D2, cyclin D3, cyclin E, cdc2, cdk2 or cdk4.
26. A method of inhibiting a cancer cell comprising a prolactin receptor, comprising contacting the cell with a complex comprising prolactin receptor ligand linked to at least one of a RNAi-inducing agent, a polynucleotide sequence encoding a polypeptide, an miRNA, an antagomir, a cytotoxic moiety, a chemotherapeutic moiety, a radioactive moiety or a nanoparticle.
27. The method of claim 26, wherein the cancer cell overexpresses prolactin receptor.
28. The method of claim 26 or claim 27, wherein the cancer cell is an ovarian cancer cell or a breast cancer cell.
29. A method of detecting a cancer cell comprising a prolactin receptor comprising: contacting a tissue suspected of comprising a cancer cell with a complex comprising a prolactin receptor ligand coupled to a marker; detecting levels of the marker present in the tissue; and correlating elevated levels of marker relative to control tissue with the presence of a cancer cell in the tissue.
30. The method of claim 29, wherein the cancer cell is an ovarian cancer cell or a breast cancer cell.
31. A complex comprising an agent coupled to a prolactin receptor ligand.
32. The complex of claim 31 , wherein the prolactin receptor ligand is human placental lactogen.
33. The complex of claim 31 or claim 32 wherein the agent is an RNAi-inducing agent, a polynucleotide sequence encoding a polypeptide, an miRNA, an antagomir, a cytotoxic moiety, a chemotherapeutic moiety, a radioactive moiety, an imaging moiety or a nanoparticle.