DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/08/26 has been entered.
Claim Status
Applicant’s reply filed on 06/04/2026 is acknowledged. Claim 25 has been amended. Claims 1-24 and 27-33 are cancelled.
Claims 25-26 and 34-49 are pending and under examination.
Rejections Withdrawn
All rejections in the Office Action dated 02/10/2026 are withdrawn in view of claim amendments filed 06/04/2026 and abandonment of co-pending Applications 17/414,971 and 18/285,664.
New Rejections Necessitated by Amendment
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.
U.S. Patent No. 11,352,430
Claims 25-26, 34-46, and 48-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,352,430 in view of Cheung (US2016/0166685A1, published 06/16/2016) and Fromm (J Immunother Cancer. 2018 Dec 18;6(1):149).
Regarding instant claims 25-26 and 48-49, pertaining to a bifunctional molecule comprising or consisting of a humanized anti-PD-1 antibody covalently linked to the N-terminus of OX40L as a fusion protein, ‘430 claims a humanized monoclonal anti-human-PD-1 antibody or an antigen-binding fragment thereof comprising: (a) a VH comprising or consisting of an amino acid sequence of SEQ ID NO: 21; and (b) a VL comprising or consisting of an amino acid sequence of SEQ ID NO: 24, wherein the antibody or antigen binding fragment thereof is an antagonist of the binding of human PD-L1 and/or PD-L2 to human PD-1 (see claim 1). SEQ ID NO: 21 of Patent ‘430: shares 100% identity with instant SEQ ID NO: 24SEQ ID NO: 24 of Patent ‘430: shares 100% identity with instant SEQ ID NO: 28, Patent ‘430 further claims the antibody, antigen binding fragment or composition administered in combination with an additional therapeutic (see claim 14).
Regarding instant claims 34-36, wherein the antibody of the bifunctional antibody of claim 25 comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgGi, IgG2, IgG3 or IgG4 heavy chain constant domain (claim 34), wherein the heavy chain constant domain is derived from IgG1 (claim 35), or wherein the heavy chain constant domain is derived from IgG4 (claim 36), ‘430 claims 3-5 claim the antibody of the disclosure comprises a light chain constant domain derived from a human kappa light chain and heavy chain constant domain derived from human IgG1 or IgG4.
Regarding instant claims 37-40, pertaining to an isolated nucleic acid sequence encoding the bifunctional molecule of claim 25 (claim 37), a vector comprising the nucleic acid (claim 38), a host cell comprising the nucleic acid or vector (claim 39), and a method for producing the bifunctional molecule comprising culturing the host cell (claim 40), ‘430 claims 7-10 disclose an isolated nucleic acid encoding the antibody of their disclosure, a vector, host cell, and method for producing the antibody comprising culturing the host cell.
Regarding instant claims 41 and 42, pertaining to a pharmaceutical composition comprising the bifunctional molecule of claim 25 (claim 41) and further comprising an additional therapeutic agent selected from the disclosed list of claim 42, ‘430 claim 11 discloses a pharmaceutical composition comprising the anti-PD-1 antibody and ‘430 claim 14 discloses the antibody is administered in combination with radiotherapy.
Regarding instant claims 43 and 44, pertaining to a method of treating cancer comprising the administration of a pharmaceutical composition comprising the bifunctional molecule (claim 43) and wherein the cancer is selected from the disclosed list of claim 44, ‘430 claim 12 recites a method of treating cancer comprising administering the anti-PD-1 of the disclosure to a subject having cancer, wherein the cancer is selected from the group consisting of malignant mesothelioma, colorectal cancer, and hepatocellular carcinoma.
Regarding instant claim 45, wherein the method of treating cancer of claim 43 comprises administration of the bifunctional molecule in combination radiotherapy or an additional therapeutic agent, ‘430 claim 14 discloses the anti-PD-1 antibody is administered in combination with radiotherapy.
Patent ‘430 does not teach: (1) a bifunctional molecule comprising or consisting of the humanized anti-PD1 antibody of the disclosure linked to OX40L a fusion protein or (2) use of the fusion protein to treat infectious disease.
These deficiencies are taught by the combined teachings of Fromm and Cheung.
The disclosure of Cheung is directed to a method for treating cancer comprising administering a PD-1 axis binding antagonist and an OX40 binding agonist (see Abstract). Cheung teaches that OX40 agonism and PD-1 antagonism individually enhance effector T cell function and proposes combined therapy to promote T cell function in response to tumors and infection (summarized in [0543]-[0544]). Indeed, they demonstrate in an exemplary treatment protocol a synergistic effect of coadministration of sub-therapeutic doses of anti-OX40 agonist antibody and an anti-PDL1 antagonist antibody (Fig. 7A and 7B).
Regarding the bifunctional molecule of instant claim 25, pertaining to the fusion of OX40L to the anti-PD-1 antibody, Cheung teaches a method for treating for delaying progression of cancer comprising administering a PD-1 axis binding antagonist and an OX40 binding agonist (Pg. 89, claim 1), wherein the PD-1 axis binding antagonist is an anti-PD-1 antibody (Pg. 89, claim 20 and 21) and wherein the OX40 binding agonist is an OX40L-Fc protein (Pg. 89, claims 40 and 44).
Regarding instant claim 46, pertaining to a method of treating infectious disease comprising administration of a composition comprising the anti-PD-1 antibody-Fc-OX40L bifunctional molecule, Cheung teaches the treatment method comprising administration of a PD-1 antagonist and OX40 agonist can be used to treat viral infection ([0017], Lines 1-3).
The disclosure of Fromm is directed to a PD-1-Fc-OX40L fusion protein which provides potent stimulation of OX40 signaling and PD1:PD-L1/L2 blockade (Abstract). Fromm demonstrates that the fusion protein PD1-Fc-OX40L led to functional activation of mouse and human T cells in vitro, and significantly outperformed PD-1/L1 blockade monotherapy, OX40 agonist monotherapy and even, surprisingly, the combination of antibody mediated PD-1/L1 blockade combined with OX40 agonist therapy (Pg. 14, Right column, Lines 6-11, see also Fig. 5).
Regarding the bi-functional molecule of instant claim 25, pertaining to the limitation that the bifunctional molecule comprises or consists of a humanized anti-PD-1 antibody covalently linked to the N-terminal end of the immunotherapeutic agent OX40L, Fromm teaches the PD-1-Fc-OX40L fusion protein comprising a PD-1 ECD fused to the N-terminal end of OX40L. While the PD-1 portion of the Fromm’s fusion protein is PD-1 ECD and not an anti-PD-1 antibody, the art is functionally analogous to the instant invention because the PD-1 ECD antagonizes the PD-1:PD-L1/L2 axis and provides motivation to make an analogous fusion protein by linking OX40L to an antagonistic anti-PD-1 antibody such as that disclosed in ‘430.
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the humanized monoclonal anti-human-PD-1 antibody of Patent ‘430 by (1) generating a bifunctional molecule comprising or consisting of the humanized anti-PD1 antibody of ‘430 linked to OX40L a fusion protein as taught by Cheung and Fromm or (2) to use of the fusion protein to treat infectious disease as taught by Cheung.
One would have been motivated to do so because Cheung teaches a synergistic anti-tumorigenic effect of combining OX40 agonism and PD-1 antagonism and Fromm teaches a fusion protein comprising an OX40L fused to a PD-1 domain which funtions to stimulate OX40 signaling and antagonize the PD-1:PD-L1/L2 axis. Together they provide the motivation to co-administer OX40L and an anti-PD-1 antibody for a synergistic effect on T cell function (as taught by Cheung) and propose that the agents can be co-administered as fusion protein rather than as separate agents (as taught by Fromm). There would be an expectation of success in making the fusion as the anti-PD-1 antibody and OX40L could readily be fused together using genetic methods known at the time of filing. There would be an expectation of success in using the a bifunctional molecule comprising the anti-PD-1 antibody of ‘430 and the OX40L because Cheung and Fromm teach the synergistic effect of co-administration of a PD-1:PD-L1/L2 antagonist and OX40L
Claims 25-26 and 34-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,352,430 in view of Cheung (US2016/0166685A1, published 06/16/2016) and Fromm (J Immunother Cancer. 2018 Dec 18;6(1):149) as applied to claims 25-26, 34-46, and 48-49 above and further in view of Publicover (Sci Transl Med. 2018 Mar 21;10(433):eaah5766).
The combined teachings of Patent ‘430, Cheung, and Fromm teach a method of treating infection disease comprising the administration of a pharmaceutical composition comprising a bifunctional molecule comprising (a) a humanized anti-human PD-1 antibody and (b) OX40L wherein the C-terminal end of the antibody is covalently linked to OX40L as a fusion protein.
The combined teachings of Patent ‘430, Cheung, and Fromm do not teach the infectious disease is caused by a virus selected from the list disclosed in claim 47.
This deficiency is taught by Publicover.
The disclosure of Publicover is directed to investigating the role of OX40 in hepatitis B virus (HBV) clearance and persistence (see Abstract). Publicover teaches patients with acute HBV infection that are able to clear HBV have significantly increased percentages of PBMC-derived T CD4+ T cells and the CD4+ T cells express high levels of OX40 (Fig. 6C). They also demonstrated in a pre-clinical mouse model that mice that were administration an OX40 agonist antibody experienced transient hepatitis and generated detectable HBV-specific T cell response, whereas mice that received isotype controls did not (Fig. 5 F-H and Pg. 5, entire left column and Lines 1-3 of right column).
Regarding instant claim 47, wherein the infection disease is caused by a virus selected from the list that includes hepatitis virus, Publicover teaches that OX40 expression correlates with the ability to clear HBV infection and provides modest pre-clinical evidence that OX40 agonism can be used therapeutically to augment HBV-specific T cell responses (see Fig. 5F-H).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the method of treating infectious disease of Patent ‘430, Cheung and Fromm with the teachings of Publicover by administering the bifunctional molecule specifically to patients with HBV (which reads on “hepatitis virus” in instant claim 47 line 2). One would have been motivated to do so because ‘480, Cheung, and Fromm teach administration of the bifunctional molecule to treat viral infection, but do not indicate a specific virus. Publicover teaches the correlation between OX40 expression and clearance of HBV infection and provides modest evidence that OX40 agonism augments anti-viral T cell responses. There would be an expectation of success in combining the methods of ‘430, Cheung and Fromm with the teachings of Publicover resulting in administration of the bifunctional anti-PD-1/OX4OL fusion protein to HBV patients because Publicover teaches the putative efficacy of OX40 agonism in clearing HBV infection.
U.S. Patent No. 12,331,118
Claims 25, 34-46, and 48-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,331,118 in view of Cheung (US2016/0166685A1, published 06/16/2016) and Fromm (J Immunother Cancer. 2018 Dec 18;6(1):149).
Regarding instant claims 25 and 48-49, pertaining to a bifunctional molecule comprising or consisting of a humanized anti-PD-1 antibody covalently linked to the N-terminus of OX40L as a fusion protein, ’118 claim 1 claims a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a humanized monoclonal anti-human-PD-1 antibody or an antigen-binding fragment thereof comprising:
the HCDR1 comprises an amino acid sequence of SEQ ID NO: 1 (see claim 1; shares 100% identity with instant SEQ ID NO: 1);
the HCDR2 comprises an amino acid sequence of SEQ ID NO: 2 (see claim 1; shares 100% identity with instant SEQ ID NO: 2);
the HCDR3 comprises an amino acid sequence of SEQ ID NOs: 9 (see claim 1; shares 100% identity with instant SEQ ID NO: 10);
the LCDR1 comprises an amino acid sequence of SEQ ID NOs: 12 (see claim 1; shares 100% identity with instant SEQ ID NO: 14);
the LCDR2 comprises an amino acid sequence of SEQ ID NO: 13 (see claim 1; shares 100% identity with instant SEQ ID NO: 15);
the LCDR3 comprises an amino acid sequence of SEQ ID NO: 14 (see claim 1; shares 100% identity with instant SEQ ID NO: 16)
Regarding instant claims 34-36, wherein the antibody of the bifunctional antibody of claim 25 comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgGi, IgG2, IgG3 or IgG4 heavy chain constant domain (claim 34), wherein the heavy chain constant domain is derived from IgG1 (claim 35), or wherein the heavy chain constant domain is derived from IgG4 (claim 36), ‘118 claims 3-5 claim the anti-PD-1 antibody of the disclosure comprises a light chain constant domain derived from a human kappa light chain and heavy chain constant domain derived from human IgG1 or IgG4.
Regarding instant claims 41 and 42, pertaining to a pharmaceutical composition comprising the bifunctional molecule of claim 25 (claim 41) and further comprising an additional therapeutic agent selected from the disclosed list of claim 42, ‘118 claims 1 and 2 claim a pharmaceutical composition comprising the anti-PD-1 antibody of the disclosure and ‘118 claim 8 recites the pharmaceutical composition is administered in combination with radiotherapy.
Regarding instant claims 43 and 44, pertaining to a method of treating cancer comprising the administration of a pharmaceutical composition comprising the bifunctional molecule (claim 43) and wherein the cancer is selected from the disclosed list of claim 44, ‘118 claim 6 recites a method of treating cancer comprising administering the pharmaceutical composition comprising the anti-PD-1 antibody to a subject having cancer, wherein the cancer is malignant mesothelioma, colorectal cancer and hepatocellular carcinoma.
Regarding instant claim 45, wherein the method of treating cancer of claim 43 comprises administration of the bifunctional molecule in combination radiotherapy or an additional therapeutic agent, ‘118 claim 8 recites the pharmaceutical composition is administered in combination with radiotherapy.
Patent ‘118 does not teach: (1) a fusion protein comprising the PD-1 linked to OX40L, (2) an isolated nucleic acid, vector, host cell comprising the vector and method of generation the bifunctional molecule or (3) the fusion protein is used to treat infectious disease.
These deficiencies are taught by the combined teachings of Fromm and Cheung.
The disclosure of Cheung is directed to a method for treating cancer comprising administering a PD-1 axis binding antagonist and an OX40 binding agonist (see Abstract). Cheung teaches that OX40 agonism and PD-1 antagonism individually enhance effector T cell function and proposes combined therapy to promote T cell function in response to tumors and infection (summarized in [0543]-[0544]). Indeed, they demonstrate in an exemplary treatment protocol a synergistic effect of coadministration of sub-therapeutic doses of anti-OX40 agonist antibody and an anti-PDL1 antagonist antibody (Fig. 7A and 7B).
Regarding the bifunctional molecule of instant claim 25, pertaining to the fusion of OX40L to the anti-PD-1 antibody, Cheung teaches a method for treating for delaying progression of cancer comprising administering a PD-1 axis binding antagonist and an OX40 binding agonist (Pg. 89, claim 1), wherein the PD-1 axis binding antagonist is an anti-PD-1 antibody (Pg. 89, claim 20 and 21) and wherein the OX40 binding agonist is an OX40L-Fc protein (Pg. 89, claims 40 and 44).
Regarding instant claim 46, pertaining to a method of treating infectious disease comprising administration of a composition comprising the anti-PD-1 antibody-Fc-OX40L bifunctional molecule, Cheung teaches the treatment method comprising administration of a PD-1 antagonist and OX40 agonist can be used to treat viral infection ([0017], Lines 1-3).
The disclosure of Fromm is directed to a PD-1-Fc-OX40L fusion protein which provides potent stimulation of OX40 signaling and PD1:PD-L1/L2 blockade (Abstract). Fromm demonstrates that the fusion protein PD1-Fc-OX40L led to functional activation of mouse and human T cells in vitro, and significantly outperformed PD-1/L1 blockade monotherapy, OX40 agonist monotherapy and even, surprisingly, the combination of antibody mediated PD-1/L1 blockade combined with OX40 agonist therapy (Pg. 14, Right column, Lines 6-11, see also Fig. 5).
Regarding the bi-functional molecule of instant claim 25, pertaining to the limitation that the bifunctional molecule comprises or consists of a humanized anti-PD-1 antibody covalently linked to the N-terminal end of the immunotherapeutic agent OX40L, Fromm teaches the PD-1-Fc-OX40L fusion protein comprising a PD-1 ECD fused to the N-terminal end of OX40L. While the PD-1 portion of the Fromm’s fusion protein is PD-1 ECD and not an anti-PD-1 antibody, the art is functionally analogous to the instant invention because the PD-1 ECD antagonizes the PD-1:PD-L1/L2 axis and provides motivation to make an analogous fusion protein by linking OX40L to an antagonistic anti-PD-1 antibody such as that disclosed in ‘118.
Regarding instant claims 37-40, pertaining to an isolated nucleic acid sequence encoding the bifunctional molecule of claim 25 (claim 37), a vector comprising the nucleic acid (claim 38), a host cell comprising the nucleic acid or vector (claim 39), and a method for producing the bifunctional molecule comprising culturing the host cell (claim 40), Fromm teaches recombinant protein production comprising the coding sequences of the fusion protein cloned into an expression vector and transiently transfected into mammalian cell (“host cells”) and purified using affinity chromatography (Pg. 2, Methods, Antibody and recombinant protein production and purification).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the humanized monoclonal anti-human-PD-1 antibody of Patent ‘430 by (1) generating a bifunctional molecule comprising or consisting of the humanized anti-PD1 antibody of ‘430 linked to OX40L a fusion protein as taught by Cheung and Fromm, (2) generating the bifunctional molecule using recombinant DNA methods known in the art, and (3) to use of the fusion protein to treat infectious disease as taught by Cheung.
One would have been motivated to do so because Cheung teaches a synergistic anti-tumorigenic effect of combining OX40 agonism and PD-1 antagonism and Fromm teaches a fusion protein comprising an OX40L fused to a PD-1 domain which functions to stimulate OX40 signaling and antagonize the PD-1:PD-L1/L2 axis. Together they provide the motivation to co-administer OX40L and an anti-PD-1 antibody for a synergistic effect on T cell function (as taught by Cheung) and propose that the agents can be co-administered as fusion protein rather than as separate agents (as taught by Fromm). There would be an expectation of success in making the fusion as the anti-PD-1 antibody and OX40L could readily be fused together using genetic methods known at the time of filing. There would be an expectation of success in using the a bifunctional molecule comprising the anti-PD-1 antibody of ‘118 and the OX40L because Cheung and Fromm teach the synergistic effect of co-administration of a PD-1:PD-L1/L2 antagonist and OX40L.
Claims 25 and 34-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,331,118 in view of Cheung (US2016/0166685A1, published 06/16/2016) and Fromm (J Immunother Cancer. 2018 Dec 18;6(1):149). as applied to claims 25, 34-46, and 48-49 above and further in view of Publicover (Sci Transl Med. 2018 Mar 21;10(433):eaah5766).
The combined teachings of Patent ‘118, Cheung, and Fromm teach a method of treating infection disease comprising the administration of a pharmaceutical composition comprising a bifunctional molecule comprising (a) a humanized anti-human PD-1 antibody and (b) OX40L wherein the C-terminal end of the antibody is covalently linked to OX40L as a fusion protein.
The combined teachings of Patent ‘118, Cheung, and Fromm do not teach the infectious disease is caused by a virus selected from the list disclosed in claim 47.
This deficiency is taught by Publicover.
The disclosure of Publicover is directed to investigating the role of OX40 in hepatitis B virus (HBV) clearance and persistence (see Abstract). Publicover teaches patients with acute HBV infection that are able to clear HBV have significantly increased percentages of PBMC-derived T CD4+ T cells and the CD4+ T cells express high levels of OX40 (Fig. 6C). They also demonstrated in a pre-clinical mouse model that mice that were administration an OX40 agonist antibody experienced transient hepatitis and generated detectable HBV-specific T cell response, whereas mice that received isotype controls did not (Fig. 5 F-H and Pg. 5, entire left column and Lines 1-3 of right column).
Regarding instant claim 47, wherein the infection disease is caused by a virus selected from the list that includes hepatitis virus, Publicover teaches that OX40 expression correlates with the ability to clear HBV infection and provides modest pre-clinical evidence that OX40 agonism can be used therapeutically to augment HBV-specific T cell responses (see Fig. 5F-H).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the method of treating infectious disease of Patent ‘118, Cheung and Fromm with the teachings of Publicover by administering the bifunctional molecule specifically to patients with HBV (which reads on “hepatitis virus” in instant claim 47 line 2). One would have been motivated to do so because ‘480, Cheung, and Fromm teach administration of the bifunctional molecule to treat viral infection, but do not indicate a specific virus. Publicover teaches the correlation between OX40 expression and clearance of HBV infection and provides modest evidence that OX40 agonism augments anti-viral T cell responses. There would be an expectation of success in combining the methods of ‘118, Cheung and Fromm with the teachings of Publicover resulting in administration of the bifunctional anti-PD-1/OX4OL fusion protein to HBV patients because Publicover teaches the putative efficacy of OX40 agonism in clearing HBV infection.
Application No. 17/414,970 (Notice of Allowance Mailed 09/29/2026)
Claims 25-26, 34-46, and 48-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34-59 of copending Application No. 17/414,970 in view of Cheung (US2016/0166685A1, published 06/16/2016) and Fromm (J Immunother Cancer. 2018 Dec 18;6(1):149).
Regarding instant claims 25-26 and 48-49, pertaining to a bifunctional molecule comprising or consisting of a humanized anti-PD-1 antibody covalently linked to the N-terminus of OX40L as a fusion protein, ‘970 claim 37-39 recite a bifunctional molecule comprising a humanized anti-human PD-1 antibody or an antigen-binding fragment thereof, which comprises: (1) a heavy chain variable domain (VH) comprising a HCDR1, a HCDR2 and a HCDR3 of SEQ ID NO: 19, 22, or 24, which are identical to instant SEQ ID NO: 19, 22, and 24 and (2) a light chain variable domain (VL) comprising a LCDR1, a LCDR2 and a LCDR3 of SEQ ID NO: 28, which is identical to instant SEQ ID NO: 28.
Regarding instant claims 34-36, wherein the antibody of the bifunctional antibody of claim 25 comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgGi, IgG2, IgG3 or IgG4 heavy chain constant domain (claim 34), wherein the heavy chain constant domain is derived from IgG1 (claim 35), or wherein the heavy chain constant domain is derived from IgG4 (claim 36), ‘970 claims 46 and 47 claim the anti-PD-1 antibody of the disclosure comprises a light chain constant domain derived from a human kappa light chain and heavy chain constant domain derived from human IgG1 or IgG4.
Regarding instant claims 37-40, pertaining to an isolated nucleic acid sequence encoding the bifunctional molecule of claim 25 (claim 37), a vector comprising the nucleic acid (claim 38), a host cell comprising the nucleic acid or vector (claim 39), and a method for producing the bifunctional molecule comprising culturing the host cell (claim 40), ‘970 claims 50-53 disclose an isolated nucleic acid encoding the antibody of their disclosure, a vector, host cell, and method for producing the antibody comprising culturing the host cell.
Regarding instant claims 41 and 42, pertaining to a pharmaceutical composition comprising the bifunctional molecule of claim 25 (claim 41) and further comprising an additional therapeutic agent selected from the disclosed list of claim 42, ‘970 claim 54 discloses a pharmaceutical composition comprising the anti-PD-1 antibody and ‘430 claim 57 discloses the antibody is administered in combination with radiotherapy.
Regarding instant claims 43 and 44, pertaining to a method of treating cancer comprising the administration of a pharmaceutical composition comprising the bifunctional molecule (claim 43) and wherein the cancer is selected from the disclosed list of claim 44, ‘970 claim 55 recite a method of treating cancer comprising the administration of a pharmaceutical composition comprising the bifunctional molecule of the disclosure and ‘970 claim 56 discloses the cancer is selected from a list that is coextensive with the list of instant claim 44.
Regarding instant claim 45, wherein the method of treating cancer of claim 43 comprises administration of the bifunctional molecule in combination radiotherapy or an additional therapeutic agent, ‘970 claim 57 claims the pharmaceutical composition is administered in combination with radiotherapy or an additional therapeutic selected from list that is coextensive with instant claim 45.
Regarding instant claim 46, pertaining to a method of treating infectious disease comprising administration of a composition comprising the anti-PD-1 antibody-Fc-OX40L bifunctional molecule, ‘970 claim 58 claims a method of treating infection disease comprising administration of the pharmaceutical composition comprising the bifunctional molecule of the disclosure.
Regarding instant claim 47, wherein the infection disease is caused by a virus selected from the disclosed list, ‘970 claim 59 discloses the infection disease is selected list consisting of HIV, hepatitis virus, herpes virus, adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
Application ‘970 does not teach a bifunctional molecule comprising or consisting of the humanized anti-PD1 antibody of the disclosure linked to OX40L a fusion protein.
This deficiency is taught by the combined teachings of Fromm and Cheung.
The disclosure of Cheung is directed to a method for treating cancer comprising administering a PD-1 axis binding antagonist and an OX40 binding agonist (see Abstract). Cheung teaches that OX40 agonism and PD-1 antagonism individually enhance effector T cell function and proposes combined therapy to promote T cell function in response to tumors and infection (summarized in [0543]-[0544]). Indeed, they demonstrate in an exemplary treatment protocol a synergistic effect of coadministration of sub-therapeutic doses of anti-OX40 agonist antibody and an anti-PDL1 antagonist antibody (Fig. 7A and 7B).
Regarding the bifunctional molecule of instant claim 25, pertaining to the fusion of OX40L to the anti-PD-1 antibody, Cheung teaches a method for treating for delaying progression of cancer comprising administering a PD-1 axis binding antagonist and an OX40 binding agonist (Pg. 89, claim 1), wherein the PD-1 axis binding antagonist is an anti-PD-1 antibody (Pg. 89, claim 20 and 21) and wherein the OX40 binding agonist is an OX40L-Fc protein (Pg. 89, claims 40 and 44).
The disclosure of Fromm is directed to a PD-1-Fc-OX40L fusion protein which provides potent stimulation of OX40 signaling and PD1:PD-L1/L2 blockade (Abstract). Fromm demonstrates that the fusion protein PD1-Fc-OX40L led to functional activation of mouse and human T cells in vitro, and significantly outperformed PD-1/L1 blockade monotherapy, OX40 agonist monotherapy and even, surprisingly, the combination of antibody mediated PD-1/L1 blockade combined with OX40 agonist therapy (Pg. 14, Right column, Lines 6-11, see also Fig. 5).
Regarding the bi-functional molecule of instant claim 25, pertaining to the limitation that the bifunctional molecule comprises or consists of a humanized anti-PD-1 antibody covalently linked to the N-terminal end of the immunotherapeutic agent OX40L, Fromm teaches the PD-1-Fc-OX40L fusion protein comprising a PD-1 ECD fused to the N-terminal end of OX40L. While the PD-1 portion of the Fromm’s fusion protein is PD-1 ECD and not an anti-PD-1 antibody, the art is functionally analogous to the instant invention because the PD-1 ECD antagonizes the PD-1:PD-L1/L2 axis and provides motivation to make an analogous fusion protein by linking OX40L to an antagonistic anti-PD-1 antibody such as that disclosed in ‘430.
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the humanized monoclonal anti-human-PD-1 antibody of Patent ‘430 by generating a bifunctional molecule comprising or consisting of the humanized anti-PD1 antibody of ‘970 linked to OX40L a fusion protein as taught by Cheung and Fromm.
One would have been motivated to do so because Cheung teaches a synergistic anti-tumorigenic effect of combining OX40 agonism and PD-1 antagonism and Fromm teaches a fusion protein comprising an OX40L fused to a PD-1 domain which funtions to stimulate OX40 signaling and antagonize the PD-1:PD-L1/L2 axis. Together they provide the motivation to co-administer OX40L and an anti-PD-1 antibody for a synergistic effect on T cell function (as taught by Cheung) and propose that the agents can be co-administered as fusion protein rather than as separate agents (as taught by Fromm). There would be an expectation of success in making the fusion as the anti-PD-1 antibody and OX40L could readily be fused together using genetic methods known at the time of filing. There would be an expectation of success in using the a bifunctional molecule comprising the anti-PD-1 antibody of ‘970 and the OX40L because Cheung and Fromm teach the synergistic effect of co-administration of a PD-1:PD-L1/L2 antagonist and OX40L.
This is a provisional nonstatutory double patenting rejection.
Application No. 17/785,427
Claims 25-26, 34-46, and 48-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25-48 of copending Application No. 17/785,427 in view of Cheung (US2016/0166685A1, published 06/16/2016) and Fromm (J Immunother Cancer. 2018 Dec 18;6(1):149).
Regarding instant claims 25-26 and 48-49, pertaining to a bifunctional molecule comprising or consisting of a humanized anti-PD-1 antibody covalently linked to the N-terminus of OX40L as a fusion protein, ‘427 claims a bifunctional molecule comprising an IL-7 variant conjugated to a binding moiety (see claim 25), wherein the binding moiety binds to PD-1 (see claims 32-34; reads on instant claim 25), and wherein the N-terminus of the IL-7 variant is fused to the C-terminus of the heavy or light chain constant domain of the antibody or antibody fragment, optionally by a peptide linker (see claim 35; reads on instant claim 25 element b). Application ‘427 further claims the anti-human PD-1 antibody, wherein:
the HCDR1 comprises an amino acid sequence of SEQ ID NO: 51 (see claim 42; shares 100% identity with instant SEQ ID NO: 1);
the HCDR2 comprises an amino acid sequence of SEQ ID NO: 53 (see claim 42; shares 100% identity with instant SEQ ID NO: 2);
the HCDR3 comprises an amino acid sequence of SEQ ID NOs: 56, 58, and 61 (see claim 42; shares 100% identity with instant SEQ ID NO: 5, 8, and 10, respectively);
the LCDR1 comprises an amino acid sequence of SEQ ID NOs: 65 (see claim 42; shares 100% identity with instant SEQ ID NO: 14);
the LCDR2 comprises an amino acid sequence of SEQ ID NO: 66 (see claim 42; shares 100% identity with instant SEQ ID NO: 15);
the LCDR3 comprises an amino acid sequence of SEQ ID NO: 16 (see claim 42; shares 100% identity with instant SEQ ID NO: 16; reads on instant claim 25)
the VH comprises an amino acid sequence of SEQ ID NOs: 19, 22, or 24 (see claim 43; shares 100% identity with instant SEQ ID NO: 19, 22, and 24respectively); and
the VL comprises an amino acid sequence of SEQ ID NO: 28 (see claim 43; shares 100% identity with instant SEQ ID NO: 28
Regarding instant claims 34-36, wherein the antibody of the bifunctional antibody of claim 25 comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgGi, IgG2, IgG3 or IgG4 heavy chain constant domain (claim 34), wherein the heavy chain constant domain is derived from IgG1 (claim 35), or wherein the heavy chain constant domain is derived from IgG4 (claim 36), ‘427 claim 30 and 31 claim the binding
moiety comprises a heavy chain constant domain or an Fc domain of a human lgG1 or IgG4.
Regarding instant claim 37 and 39, pertaining to an isolated nucleic acid encoding the bifunctional molecule of claim 25 (claim 37) and a host cell comprising the nucleic acid (claim 39), ‘427 claims 45 and 46 recite an isolated nucleic acid encoding the bifunctional molecule of the disclosure and a host cell comprising the isolated nucleic acid.
Regarding instant claims 41, pertaining to a pharmaceutical composition comprising the bifunctional molecule of claim 25, ‘427 claim 47 recites a pharmaceutical composition comprising the bifunctional molecule of the disclosure.
Regarding instant claims 43 and 46, pertaining to a method of treating cancer (claim 43) and a method of treating infection disease (claim 46) comprising the administration of a pharmaceutical composition comprising the anti-PD-1 antibody-Fc-OX40L bifunctional molecule, ‘427 claim 48 recites a method of treating cancer or an infection disease comprising the administration of the bifunctional molecule to a subject having cancer of an infection disease.
Application ‘427 does not teach: (1) a bifunctional molecule comprising or consisting of the humanized anti-PD1 antibody of the disclosure linked to OX40L a fusion protein, (2) that the pharmaceutical composition and method of treating cancer comprise an additional therapeutic agent, or (3) a vector and method of generation the bifunctional molecule comprising culturing a host cell expressing the vector.
These deficiencies are taught by the combined teachings of Fromm and Cheung.
The disclosure of Cheung is directed to a method for treating cancer comprising administering a PD-1 axis binding antagonist and an OX40 binding agonist (see Abstract). Cheung teaches that OX40 agonism and PD-1 antagonism individually enhance effector T cell function and proposes combined therapy to promote T cell function in response to tumors and infection (summarized in [0543]-[0544]). Indeed, they demonstrate in an exemplary treatment protocol a synergistic effect of coadministration of sub-therapeutic doses of anti-OX40 agonist antibody and an anti-PDL1 antagonist antibody (Fig. 7A and 7B).
Regarding the bifunctional molecule of instant claim 25, pertaining to the fusion of OX40L to the anti-PD-1 antibody, Cheung teaches a method for treating for delaying progression of cancer comprising administering a PD-1 axis binding antagonist and an OX40 binding agonist (Pg. 89, claim 1), wherein the PD-1 axis binding antagonist is an anti-PD-1 antibody (Pg. 89, claim 20 and 21) and wherein the OX40 binding agonist is an OX40L-Fc protein (Pg. 89, claims 40 and 44).
Regarding instant claim 42 and 45, wherein the pharmaceutical composition of claim 41 further comprises an additional therapeutic agent (claim 42) and wherein the method of treating cancer of claim 43 comprises administration of the bifunctional molecule in combination radiotherapy or an additional therapeutic agent (claim 45), Cheung teaches the composition and method of the disclosure further comprise administering a chemotherapeutic agent for treating or delaying the progression of cancer in an individual (reads on instant claims 42 and 45 “angiogenesis inhibitors”).
Regarding instant claim 44, wherein the cancer of the method of claim 43 is selected from the disclosed list, Cheung teaches wherein the cancer treated in their method is breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, colon cancer, kidney cancer, esophageal cancer, prostate cancer, colorectal cancer, glioblastoma, neuroblastoma, or hepatocellular carcinoma.
The disclosure of Fromm is directed to a PD-1-Fc-OX40L fusion protein which provides potent stimulation of OX40 signaling and PD1:PD-L1/L2 blockade (Abstract). Fromm demonstrates that the fusion protein PD1-Fc-OX40L led to functional activation of mouse and human T cells in vitro, and significantly outperformed PD-1/L1 blockade monotherapy, OX40 agonist monotherapy and even, surprisingly, the combination of antibody mediated PD-1/L1 blockade combined with OX40 agonist therapy (Pg. 14, Right column, Lines 6-11, see also Fig. 5).
Regarding the bi-functional molecule of instant claim 25, pertaining to the limitation that the bifunctional molecule comprises or consists of a humanized anti-PD-1 antibody covalently linked to the N-terminal end of the immunotherapeutic agent OX40L, Fromm teaches the PD-1-Fc-OX40L fusion protein comprising a PD-1 ECD fused to the N-terminal end of OX40L. While the PD-1 portion of the Fromm’s fusion protein is PD-1 ECD and not an anti-PD-1 antibody, the art is functionally analogous to the instant invention because the PD-1 ECD antagonizes the PD-1:PD-L1/L2 axis and provides motivation to make an analogous fusion protein by linking OX40L to an antagonistic anti-PD-1 antibody such as that disclosed in ‘430.
Regarding instant claims 38 and 40, pertaining to a vector comprising the nucleic acid encoding the bifunctional molecule of claim 25 (claim 38) and a method for producing the bifunctional molecule comprising culturing the host cell of claim 39 (claim 40), Fromm teaches recombinant protein production comprising the coding sequences of the fusion protein cloned into an expression vector and transiently transfected into mammalian cell (“host cells”) and purified using affinity chromatography (Pg. 2, Methods, Antibody and recombinant protein production and purification).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the humanized monoclonal anti-human-PD-1 antibody of Patent ‘430 by (1) generating a bifunctional molecule comprising or consisting of the humanized anti-PD1 antibody of ‘427 linked to OX40L a fusion protein as taught by Cheung and Fromm, (2) generating the bifunctional molecule using recombinant DNA methods known in the art, and (3) co-administering the bifunctional molecule with additional therapeutics known in the art as taught by Cheung.
One would have been motivated to do so because Cheung teaches a synergistic anti-tumorigenic effect of combining OX40 agonism and PD-1 antagonism and Fromm teaches a fusion protein comprising an OX40L fused to a PD-1 domain which functions to stimulate OX40 signaling and antagonize the PD-1:PD-L1/L2 axis. Together they provide the motivation to co-administer OX40L and an anti-PD-1 antibody for a synergistic effect on T cell function (as taught by Cheung) and propose that the agents can be co-administered as fusion protein rather than as separate agents (as taught by Fromm). There would be an expectation of success in making the fusion as the anti-PD-1 antibody and OX40L could readily be fused together using genetic methods known at the time of filing. There would be an expectation of success in using the a bifunctional molecule comprising the anti-PD-1 antibody of ‘427 and the OX40L because Cheung and Fromm teach the synergistic effect of co-administration of a PD-1:PD-L1/L2 antagonist and OX40L.
This is a provisional nonstatutory double patenting rejection.
Claims 25-26 and 34-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25-48 of copending Application No. 17/785,427 in view of Cheung (US2016/0166685A1, published 06/16/2016) and Fromm (J Immunother Cancer. 2018 Dec 18;6(1):149) as applied to claims 25-26, 34-46, and 48-49 above and further in view of Publicover (Sci Transl Med. 2018 Mar 21;10(433):eaah5766).
The combined teachings of Application ‘427, Cheung, and Fromm teach a method of treating infection disease comprising the administration of a pharmaceutical composition comprising a bifunctional molecule comprising (a) a humanized anti-human PD-1 antibody and (b) OX40L wherein the C-terminal end of the antibody is covalently linked to OX40L as a fusion protein.
The combined teachings of Application ‘427, Cheung, and Fromm do not teach the infectious disease is caused by a virus selected from the list disclosed in claim 47.
This deficiency is taught by Publicover.
The disclosure of Publicover is directed to investigating the role of OX40 in hepatitis B virus (HBV) clearance and persistence (see Abstract). Publicover teaches patients with acute HBV infection that are able to clear HBV have significantly increased percentages of PBMC-derived T CD4+ T cells and the CD4+ T cells express high levels of OX40 (Fig. 6C). They also demonstrated in a pre-clinical mouse model that mice that were administered an OX40 agonist antibody experienced transient hepatitis and generated detectable HBV-specific T cell response, whereas mice that received isotype controls did not (Fig. 5 F-H and Pg. 5, entire left column and Lines 1-3 of right column).
Regarding instant claim 47, wherein the infection disease is caused by a virus selected from the list that includes hepatitis virus, Publicover teaches that OX40 expression correlates with the ability to clear HBV infection and provides modest pre-clinical evidence that OX40 agonism can be used therapeutically to augment HBV-specific T cell responses (see Fig. 5F-H).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the method of treating infectious disease of ‘427, Cheung and Fromm with the teachings of Publicover by administering the bifunctional molecule specifically to patients with HBV (which reads on “hepatitis virus” in instant claim 47 line 2). One would have been motivated to do so because ‘427, Cheung, and Fromm teach administration of the bifunctional molecule to treat viral infection, but do not indicate a specific virus. Publicover teaches the correlation between OX40 expression and clearance of HBV infection and provides modest evidence that OX40 agonism augments anti-viral T cell responses. There would be an expectation of success in combining the methods of ‘427, Cheung and Fromm with the teachings of Publicover resulting in administration of the bifunctional anti-PD-1/OX4OL fusion protein to HBV patients because Publicover teaches the putative efficacy of OX40 agonism in clearing HBV infection.
This is a provisional nonstatutory double patenting rejection.
Application No. 18/267,795
Claims 25-26 and 34-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-68 of copending Application No. 18/267,795 in view of Cheung (US2016/0166685A1, published 06/16/2016) and Fromm (J Immunother Cancer. 2018 Dec 18;6(1):149).
Regarding instant claims 25-26 and 48-49, pertaining to a bifunctional molecule comprising or consisting of a humanized anti-PD-1 antibody covalently linked to the N-terminus of OX40L as a fusion protein, claim 56 discloses the anti-PD-1 antibody of the disclosure:
the HCDR1 comprises an amino acid sequence of SEQ ID NO: 51 (see claim 42; shares 100% identity with instant SEQ ID NO: 1);
the HCDR2 comprises an amino acid sequence of SEQ ID NO: 53 (see claim 42; shares 100% identity with instant SEQ ID NO: 2);
the HCDR3 comprises an amino acid sequence of SEQ ID NOs: 56, 58, and 61 (see claim 42; shares 100% identity with instant SEQ ID NO: 5, 8, and 10, respectively);
the LCDR1 comprises an amino acid sequence of SEQ ID NOs: 65 (see claim 42; shares 100% identity with instant SEQ ID NO: 14);
the LCDR2 comprises an amino acid sequence of SEQ ID NO: 66 (see claim 42; shares 100% identity with instant SEQ ID NO: 15);
the LCDR3 comprises an amino acid sequence of SEQ ID NO: 16 (see claim 42; shares 100% identity with instant SEQ ID NO: 16; reads on instant claim 25)
the VH comprises an amino acid sequence of SEQ ID NOs: 19, 22, or 24 (see claim 43; shares 100% identity with instant SEQ ID NO: 19, 22, and 24respectively); and
the VL comprises an amino acid sequence of SEQ ID NO: 28 (see claim 43; shares 100% identity with instant SEQ ID NO: 28
Regarding instant claims 34-36, wherein the antibody of the bifunctional antibody of claim 25 comprises a light chain constant domain derived from a human kappa light chain constant domain and a heavy chain constant domain derived from a human IgGi, IgG2, IgG3 or IgG4 heavy chain constant domain (claim 34), wherein the heavy chain constant domain is derived from IgG1 (claim 35), or wherein the heavy chain constant domain is derived from IgG4 (claim 36), ‘795 claim 48 claims the bifunctional molecule comprises a heavy chain constant domain of human IgG1 or human IgG4.
Regarding instant claim 37 and 39, pertaining to an isolated nucleic acid encoding the bifunctional molecule of claim 25 (claim 37) and a host cell comprising the nucleic acid (claim 39), ‘795 claims 61 and 62 claim an isolated nucleic acid comprising the bifunctional molecule of the disclosure and a host cell comprising the isolated nucleic acid molecule.
Regarding instant claims 41 and 42, pertaining to a pharmaceutical composition comprising the bifunctional molecule of claim 25 (claim 41) and further comprising an additional therapeutic agent selected from the disclosed list of claim 42, ‘795 claim 63 recites a pharmaceutical composition comprising the bifunctional molecule of the disclosure and ‘795 claim 67 claims the treatment further comprises additional therapeutics such chemotherapy.
Regarding instant claims 43 and 44, pertaining to a method of treating cancer comprising the administration of a pharmaceutical composition comprising the bifunctional molecule (claim 43) and wherein the cancer is selected from the disclosed list of claim 44, ‘795 claim 64 and 65 recite a method of treating cancer comprising administering a therapeutically effective amount of the bifunctional molecule of the disclosure and wherein the cancer is selected from a list that includes cervical cancer as recited in instant claim 44.
Regarding instant claim 45, wherein the method of treating cancer of claim 43 comprises administration of the bifunctional molecule in combination radiotherapy or an additional therapeutic agent, ‘795 claim 67 claims the treatment method further comprises radiotherapy or other therapeutic agents.
Regarding instant claim 46, pertaining to a method of treating infectious disease comprising administration of a composition comprising the anti-PD-1 antibody-Fc-OX40L bifunctional molecule, ‘795 claim 64 claims a method of treating a viral infection comprising administering a therapeutically effective amount of the bifunctional molecule of the disclosure.
Regarding instant claim 47, wherein the infection disease is caused by a virus selected from the disclosed list, ‘795 claim 66 teaches the viral infection is HIV as recited in instant claim 47.
Application ‘970 does not teach: (1) a bifunctional molecule comprising or consisting of the humanized anti-PD1 antibody of the disclosure linked to OX40L a fusion protein or (2) a vector and method of generation the bifunctional molecule comprising culturing a host cell expressing the vector.
This deficiency is taught by the combined teachings of Fromm and Cheung.
The disclosure of Cheung is directed to a method for treating cancer comprising administering a PD-1 axis binding antagonist and an OX40 binding agonist (see Abstract). Cheung teaches that OX40 agonism and PD-1 antagonism individually enhance effector T cell function and proposes combined therapy to promote T cell function in response to tumors and infection (summarized in [0543]-[0544]). Indeed, they demonstrate in an exemplary treatment protocol a synergistic effect of coadministration of sub-therapeutic doses of anti-OX40 agonist antibody and an anti-PDL1 antagonist antibody (Fig. 7A and 7B).
Regarding the bifunctional molecule of instant claim 25, pertaining to the fusion of OX40L to the anti-PD-1 antibody, Cheung teaches a method for treating for delaying progression of cancer comprising administering a PD-1 axis binding antagonist and an OX40 binding agonist (Pg. 89, claim 1), wherein the PD-1 axis binding antagonist is an anti-PD-1 antibody (Pg. 89, claim 20 and 21) and wherein the OX40 binding agonist is an OX40L-Fc protein (Pg. 89, claims 40 and 44).
The disclosure of Fromm is directed to a PD-1-Fc-OX40L fusion protein which provides potent stimulation of OX40 signaling and PD1:PD-L1/L2 blockade (Abstract). Fromm demonstrates that the fusion protein PD1-Fc-OX40L led to functional activation of mouse and human T cells in vitro, and significantly outperformed PD-1/L1 blockade monotherapy, OX40 agonist monotherapy and even, surprisingly, the combination of antibody mediated PD-1/L1 blockade combined with OX40 agonist therapy (Pg. 14, Right column, Lines 6-11, see also Fig. 5).
Regarding the bi-functional molecule of instant claim 25, pertaining to the limitation that the bifunctional molecule comprises or consists of a humanized anti-PD-1 antibody covalently linked to the N-terminal end of the immunotherapeutic agent OX40L, Fromm teaches the PD-1-Fc-OX40L fusion protein comprising a PD-1 ECD fused to the N-terminal end of OX40L. While the PD-1 portion of the Fromm’s fusion protein is PD-1 ECD and not an anti-PD-1 antibody, the art is functionally analogous to the instant invention because the PD-1 ECD antagonizes the PD-1:PD-L1/L2 axis and provides motivation to make an analogous fusion protein by linking OX40L to an antagonistic anti-PD-1 antibody such as that disclosed in ‘795.
Regarding instant claims 38 and 40, pertaining to a vector comprising the nucleic acid encoding the bifunctional molecule of claim 25 (claim 38) and a method for producing the bifunctional molecule comprising culturing the host cell of claim 39 (claim 40), Fromm teaches recombinant protein production comprising the coding sequences of the fusion protein cloned into an expression vector and transiently transfected into mammalian cell (“host cells”) and purified using affinity chromatography (Pg. 2, Methods, Antibody and recombinant protein production and purification).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the humanized monoclonal anti-human-PD-1 antibody of Patent ‘430 by (1) generating a bifunctional molecule comprising or consisting of the humanized anti-PD1 antibody of ‘795 linked to OX40L a fusion protein as taught by Cheung and Fromm, (2) generating the bifunctional molecule using recombinant DNA methods known in the art.
One would have been motivated to do so because Cheung teaches a synergistic anti-tumorigenic effect of combining OX40 agonism and PD-1 antagonism and Fromm teaches a fusion protein comprising an OX40L fused to a PD-1 domain which functions to stimulate OX40 signaling and antagonize the PD-1:PD-L1/L2 axis. Together they provide the motivation to co-administer OX40L and an anti-PD-1 antibody for a synergistic effect on T cell function (as taught by Cheung) and propose that the agents can be co-administered as fusion protein rather than as separate agents (as taught by Fromm). There would be an expectation of success in making the fusion as the anti-PD-1 antibody and OX40L could readily be fused together using genetic methods known at the time of filing. There would be an expectation of success in using the a bifunctional molecule comprising the anti-PD-1 antibody of ‘795 and the OX40L because Cheung and Fromm teach the synergistic effect of co-administration of a PD-1:PD-L1/L2 antagonist and OX40L.
This is a provisional nonstatutory double patenting rejection.
Response to Applicant’s Remarks
In view of Applicant’s amendments to the claims, all of the nonstatutory double patenting rejections are newly presented. The crux of the rejections as currently presented is that that art teaches that it would be obvious to fuse an OX40L-Fc to an anti-PD-1 antibody, such as the anti-PD-1 antibody disclosed in the above patents and co-pending applications. While this specific anti-PD-1 antibody is not known in the prior art, it is disclosed in the above listed patents and co-pending applications. The addition of an OX40L-Fc to the anti-PD-1 antibody is obvious over the prior art therefore the instant claims remain rejected based on obviousness double-patenting.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646
