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 .
Claim Status
Applicant’s reply filed on 11/06/2025 is acknowledged. Claims 25-26 and 29-36 are amended. Claims 27-28 are canceled. Claims 48-49 are newly added
Claims 25-26, and 29-49 are pending and under examination.
Objections/Rejections Withdrawn
The following are withdrawn in view of amendments filed 11/06/2025:
Claims 25 and 26 are objected to for the use of the term “an amino acid sequence”.
Claims 25-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
All double patenting rejections set forth in the Office Action dated 05/06/2025 are updated herein as necessitated by amendment.
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.
Patent No. 11,352,430
Claims 25-26, 29, 32, and 34-49 remain/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 Codarri Deak (WO2018/184964; cited on the IDS filed June 17 2021) and Naing (Annals of Oncology, 28, xi1).
Regarding claims 25-26, 32 and 48-49, Patent ‘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).
However, Patent ‘430 does not claim that the antibody is covalently linked to an immunotherapeutic agent or fragment.
This deficiency is taught by Codarri Deak and Naing.
Codarri Deak discloses an immunoconjugate comprising (i) an antibody that binds to PD-1 and (ii) an IL-2 polypeptide (see claim 1, where IL-2 reads on “immunotherapeutic agent” in instant claim 25 and “cytokine” in instant claim 28; also reads on instant claims 32-33), wherein the C-terminal end of the antibody is covalently linked to the N-terminal end of the immunotherapeutic agent through a peptide linker (see p. 8 lines 10-13- “IL-2 polypeptide is fused at its amino-terminal amino acid to the carboxy-terminal amino acid of one of the subunits of the Fc domain, particularly the first subunit of the Fc domain, optionally through a linker peptide”). Coddari Deak further discloses: that IL-2 has the ability to expand and increase the effector functions of lymphocyte populations in vivo, making IL-2 immunotherapy an attractive treatment option for certain metastatic cancers… high-dose IL-2 treatment has been approved for use in patients with metastatic renal-cell carcinoma and malignant melanoma (see p. 2 lines 16-19); an approach, which may circumvent the problems of tumor-targeting, is to target IL-2 directly to effector cells, in particular CTLs (see p. 5 lines 1-3); PD-1 is a cell surface receptor and is expressed on activated B cells, T cells, and myeloid cells (p. 5 lines 9-10); and targeting to immune effector cells is achieved by conjugating IL-2 to an antibody that binds to PD-1 (see p. 6 lines 1-2).
Naing teaches IL-10 and PD-1 receptors are both expressed on activated and exhausted CD8+ T cells and that the cytokine IL-10 stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. Naing cites this rationale for combining AMO010 human IL-10 co-administered with an anti-PD-1 antibody (Background). Naing found that AMO010 plus nivolumab or pembrolizumab was well tolerated and responding patients had a higher degree of CD8+ T cell invigoration (Results).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art to have covalently linked an immunotherapeutic agent, such as a cytokine, as taught by Codarri Deak, and specifically IL-10 as taught by Naing to the anti-PD-1 antibody of Patent ‘430, to arrive at the instant invention. One would have been motivated to do so because covalently linking an immunotherapeutic agent to an anti-PD-1 antibody facilitates delivery of the immunotherapeutic agent directly to immune effector cells. One would have been motivated to specifically use IL-10 as the immunotherapeutic agent, as IL-10 is known in the art to stimulate cytotoxicity and proliferation in exhausted CD8+ T cells.
Regarding claims 29, Codarri Deak discloses that IL-2 is 15.5 kDa (see p. 1 line 10; reads on “wherein the immunotherapeutic agent fragment thereof has a size comprised between 10 kDa and 50 kDa” in instant claim 29).
Regarding claims 34, Patent ‘430 claims the antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment thereof 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 IgG1, IgG2, IgG3 or IgG4 heavy chain constant domain (see claim 3; reads on instant claim 34 in its entirety).
Regarding claims 35, Patent ‘430 claims the antibody or antigen-binding fragment, wherein the antibody or antigen binding fragment thereof 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 IgG1 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P33 IS; E333A; S239D/A330L/1332E; P2571/Q311; K326W/E333S; S239D/1332E/G236A; N297A; L234A/L235A; N297A + M252Y/S254T/T256E; K322A; and K444A (see claim 4; reads on instant claim 35 in its entirety).
Regarding claims 36, Patent ‘430 claims the antibody or antigen-binding fragment, wherein the antibody or antigen binding fragment thereof 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 IgG4 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P, L234A/L235A, S228P + M252Y/S254T/T256E and K444A (see claim 5; reads on instant claim 36 in its entirety).
Regarding claims 37, Patent ‘430 claims an isolated nucleic acid molecule or a group of isolated nucleic acid molecules encoding the antibody or antigen-binding fragment (see claim 7).
Regarding claims 38, Patent ‘430 claims a vector comprising the isolated nucleic acid molecule or the group of isolated nucleic acid molecules (see claim 8).
Regarding claims 39, Patent ‘430 claims a host cell comprising the isolated nucleic acid molecule and/or the group of isolated nucleic acid molecules and/or the vector comprising said nucleic acid molecule or group of nucleic acid molecules (see claim 9).
Regarding claims 40, Patent ‘430 claims a method for producing the antibody or antigen-binding fragment comprising a step of culturing the host cell and optionally a step of isolating the antibody or antigen-binding fragment (see claim 10).
Regarding claims 41, Patent ‘430 claims a pharmaceutical composition comprising the antibody or an antigen-binding fragment and a pharmaceutically acceptable carrier (see claim 11).
Regarding claims 42 and 45, Patent ‘430 claims the antibody, antigen binding fragment or composition administered in combination with a radiotherapy or an additional therapeutic (see claim 14 ; reads on instant claim 45), however does not claim the therapeutics listed in instant claims 42. Codarri Deak discloses that the immunoconjugates according to the invention may be administered in combination with one or more additional therapeutic agents, such as an immunomodulatory agent, a cytostatic agent, an inhibitor of cell adhesion, a cytotoxic agent, an activator of cell apoptosis, an agent that increases the sensitivity of cells to apoptotic inducers, a microtubule disruptor, an antimetabolite, a topoisomerase inhibitor, a DNA intercalator, an alkylating agent, a hormonal therapy, a kinase inhibitor, a receptor antagonist, an activator of tumor cell apoptosis, or an antiangiogenic agent (see p. 69 lines 15-27; reads on instant claims 42 and 45). Therefore, it would have been prima facie obvious to have administered the immunoconjugate in combination with an additional therapeutic, to arrive at the present invention, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. (See MPEP § 2143).
Regarding claims 43-44, Patent ‘430 claims a method of treating cancer comprising the administration of the pharmaceutical composition to a subject having cancer, wherein the cancer is malignant mesothelioma, colorectal cancer and hepatocellular carcinoma (see claim 12; reads on instant claims 43-44).
Regarding claims 46-47, Patent ‘430 does not claim treating (chronic) infectious disease or chronic viral infections. However, Codarri Deak discloses: a method of treating a disease in an individual, comprising administering to said individual a therapeutically effective amount of a composition comprising the immunoconjugate (see claim 35); and a method of targeting chronic viral infections (see Example 4 on p. 92- “PD- 1 expression has been described for the first time on exhausted virus-specific T cells as a consequence of chronic-exposure to viral antigens and it has been associated with T -cell inability to mount an effective anti-viral response… Indeed, the polyfunctional signature of CD4 T cells has been associated with viral-control in healthy individuals infected by CMV, EBV, Herpes Simplex virus (HSV), and HIV who remain symptoms-free for several years… In the context of chronic viral infections, we therefore developed an in-vitro assay to evaluate the effect of PD-1 and PD-L1 targeting to deliver a mutated version ofIL-2 (IL-2v) to dysfunctional antigen-specific T cells”; see also p. 93 lines 14-16- “we can conclude that delivering IL-2v to the exhausted CMV-specific CD4 T cells through the 15 PD1-IL-2v fusion protein resulted in the expansion of a long-lived protective virus-specific population characterized by the ability to co-secrete IL-2 and IFN-y”). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have developed the method of the current invention by treating disease, wherein the disease is a chronic viral infections, as the teachings of Codarri Deak suggest combining an antibody against PD-1 and the immunotherapeutic agent, IL-2, results in expansion of virus-specific T cells, and thus, may be beneficial for treating chronic viral infections, such as HIV and HSV.
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Figure 1: Sequence alignment of instant SEQ ID NO: 17 to Patent 11,352,430 SEQ ID NO: 21 (ABSS).
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Figure 2: Sequence alignment of instant SEQ ID NO: 26 aligned to Patent 11,352,430 SEQ ID NO: 24 (ABSS).
Claims 30-31 remain/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 Codarri Deak (supra) and Naing (supra), as applied to claims 25-26, 29, 32, and 34-49 above, and further in view of Sharma (Cell. 2015 Apr 9;161(2):205-14. doi: 10.1016/j.cell.2015.03.030.).
The disclosures/teachings of Patent ‘430 are discussed above and are
incorporated herein.
Regarding claims 30-31, Patent ‘430 does not claim the anti-PD-1 antibody covalently linked to a human transmembrane immune protein of type I or II or a fragment thereof. Sharma teaches: “ongoing studies on regulation of immune responses have led to the identification of multiple other immunologic pathways that may be targeted for the development of therapies, either as monotherapy or in combination strategies, for the successful treatment of cancer patients” (see p. 8 last par.); “there are ongoing clinical trials with anti-CTLA-4 (ipilimumab, BMS or tremelimumab, MedImmune/Astrazeneca) plus anti-PD-1 or anti-PD-L1 in other tumor types, with preliminary data indicating promising results, which highlight this combination as an effective immunotherapy strategy for cancer patients.” (see p. 8 par. 2); “new immune checkpoints that are being evaluated in pre-clinical tumor models and/or in the clinic with cancer patients include LAG-3, TIM-3, and VISTA, while co-stimulatory molecules include ICOS, OX40 and 4–1BB” (see p. 9 par. 1); “other clinical trials are ongoing with an antibody against LAG-3 (BMS-986016), which is also being tested in combination with anti-PD-1 (nivolumab) (NCT01968109, clinicaltrials.gov)… Pre-clinical studies indicate that TIM-3 is co-expressed with PD-1 on tumor-infiltrating lymphocytes and combination therapy targeting these two pathways improves anti-tumor immune responses. Finally, an antibody targeting VISTA was recently shown to improve anti-tumor immune responses in mice” (see p. 9 par. 2); “it is likely that combination therapy to simultaneously engage co-stimulatory pathways and limit inhibitory pathways will be a successful path forward to provide clinical benefit.” (see p. 10 par. 1).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art to have covalently linked the anti-PD-1 antibody of Patent ‘430 to an immunotherapeutic agent, such as those taught by Sharma, to arrive at the instant invention. One would have been motivated to do so because combination therapies that simultaneously target PD-1 and other inhibitory pathways or costimulatory molecules are known in the art, and are known to improve anti-tumor immune responses.
Claims 33 is 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 Linch (Front Oncol. 2015 Feb 16;5:34).The disclosures of Patent ‘430 are discussed above and are incorporated herein.
Regarding claim 33, Patent ‘430 does not disclose the immunotherapeutic agent is OX40L. This deficiency is taught by Linch who teaches that OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the points to potential opportunities for clinical translation of combinatorial immunotherapeutic strategies (Abstract). Linch teaches that OX40L-Fc fusion proteins results in tumor regression in several preclinical models (Pg. 2, right column, full paragraph 1, Lines 1-4 and Table 1). Linch teaches OX40 agonism can complement PD-1 blockade by supporting the expansion, survival, and effector function of activated CD4 and CD8 T cells that express the PD-1 receptor (Pg. 7, Left column, full paragraph 2, Lines 1-9).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art to modify the anti-PD-1 antibody of Patent ‘430 by covalently linking an OX40L therapeutic agent. One would be motivated to do so because Linch teaches OX40L administration results in tumor regression and suggest combination therapy with PD-1 blockage therapy to support the expansion, survival, and effector function of T cells.
Copending Application No. 17/414,970
Claims 25-26, 29, 32, and 34-49 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 35-59 of Copending Application No. 17/414,970 (reference application) in view of Naing (supra), as evidenced by Goodwin (PNAS 1989, 86 (1) 302-306). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Application ‘970 anticipate instant claims 25-29 and 32-46.
This is a provisional nonstatutory double patenting rejection.
Regarding claims 25-26 and 32, Application ‘970 claims a bifunctional molecule comprising: (a) 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, and (2) a light chain variable domain (VL) comprising a LCDR1, a LCDR2 and a LCDR3, and (b) a human interleukin 7 (IL-7) or a fragment or variant thereof, wherein the antibody or the fragment thereof is covalently linked to the human IL-7 or a fragment or variant thereof as a fusion protein, wherein the N-terminal end of the human IL-7 or the fragment thereof is connected to the C-terminal end of the heavy chain or of the light chain of the anti-human PD-1 antibody or the antigen-binding fragment thereof or both (see claims 35-36; reads on instant claim 32). Application ‘970 further claims the anti-human PD-1 antibody, wherein:
the HCDR1 comprises or consists of an amino acid sequence of SEQ ID NO: 1;
the HCDR2 comprises or consists of an amino acid sequence of SEQ ID NO: 2;
the HCDR3 comprises or consists of an amino acid sequence of SEQ ID NO: 3, wherein X1 is D or E and X2 is T, H, A, Y, N, E or S, which anticipates instant SEQ ID NOs: 5, 8 and 10;
the LCDR1 comprises or consists of an amino acid sequence of SEQ ID NO: 12, wherein X is G or T;
the LCDR2 comprises or consists of an amino acid sequence of SEQ ID NO: 15
the LCDR3 comprises or consists of an amino acid sequence of SEQ ID NO: 16
the VH comprises or consists of an amino acid sequence of SEQ ID NO: 24, which shares 100% identity with instant SEQ ID NO: 24 (see ’470 claim 30)
the VL comprises or consists of an amino acid sequence of SEQ ID NO: 28, which shares 100% identity with instant SEQ ID NO: 28 (see ’470 claim 30)
Regarding claim 29, Application ‘970 claims the bifunctional molecule comprising human IL-7 (see claim 35), which is known to have a molecular weight of 17.4 kDa, as evidenced by Goodwin (see abstract; reads on “wherein the immunotherapeutic agent fragment thereof has a size comprised between 10 kDa and 50 kDa” in instant claim 29).
Regarding claims 34-35, Application ‘970 claims the bifunctional molecule, wherein the antibody or antigen binding fragment thereof 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 IgG1 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P33 IS; E333A; S239D/A330L/1332E; P2571/Q311; K326W/E333S; S239D/1332E/G236A; N297A; L234A/L235A; N297A + M252Y/S254T/T256E; K322A; and K444A (see claim 46; reads on instant claims 34-35).
Regarding claims 36, Application ‘970 claims the antibody or antigen-binding fragment, wherein the antibody or antigen binding fragment thereof 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 IgG4 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P, L234A/L235A, S228P + M252Y/S254T/T256E and K444A (see claim 47; reads on instant claim 36; also reads on instant claim 34).
Regarding claims 37, Application ‘970 claims an isolated nucleic acid molecule or a group of isolated nucleic acid molecules encoding the bifunctional molecule (see claim 50).
Regarding claims 38, Application ‘970 claims a vector comprising the isolated nucleic acid molecule or the group of isolated nucleic acid molecules (see claim 51).
Regarding claims 39, Application ‘970 claims a host cell comprising the isolated nucleic acid molecule and/or the group of isolated nucleic acid molecules and/or the vector comprising said nucleic acid molecule or group of nucleic acid molecules (see claim 52).
Regarding claims 40, Application ‘970 claims a method for producing the bifunctional molecule comprising a step of culturing the host cell and optionally a step of isolating the bifunctional molecule (see claim 53).
Regarding claims 41, Application ‘970 claims a pharmaceutical composition comprising the bifunctional molecule and a pharmaceutically acceptable carrier (see claim 54).
Regarding claims 42 and 45, Application ‘970 claims the pharmaceutical composition administered in combination with radiotherapy or an additional therapeutic agent selected from the group consisting of alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, biologic response modifiers, Bruton's tyrosine kinase (BTK) inhibitors, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of apoptosis proteins (IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, microRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (PI3K) inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, hypomethylating agents, checkpoints inhibitors, peptide vaccines, epitopes or neoepitopes from tumor antigens, and combinations of one or more of these agents (see claim 57).
Regarding claims 43-44 and 47, Application ‘970 claims a method of treating cancer comprising the administration of the pharmaceutical composition to a subject in need of treatment, wherein the cancer is a hematologic malignancy or a solid tumor with expression of PD-1 and/or PD-L1 selected from hematolymphoid neoplasms, angioimmunoblastic T cell lymphoma, myelodysplastic syndrome, and acute myeloid leukemia, a cancer induced by virus or associated with immunodeficiency, Kaposi sarcoma, cervical, anal, penile and vulvar squamous cell cancer, oropharyngeal cancers, B cell non- Hodgkin lymphomas (NHL), diffuse large B-cell lymphoma, Burkitt lymphoma, plasmablastic lymphoma, primary central nervous system lymphoma, HHV-8 primary effusion lymphoma, classic Hodgkin lymphoma, lymphoproliferative disorders, hepatocellular carcinoma, Merkel cell carcinoma, cancer associated with human immunodeficiency virus infection (HIV) infection, metastatic or non-metastatic cancer, Melanoma, malignant mesothelioma, Non-Small Cell Lung Cancer, Renal Cell Carcinoma, Hodgkin's Lymphoma, Head and Neck Cancer, Urothelial Carcinoma, Colorectal Cancer, Hepatocellular Carcinoma, Small Cell Lung Cancer, Metastatic Merkel Cell Carcinoma, Gastric or Gastroesophageal cancers and Cervical Cancer (see claims 55-56).
Regarding claims 46, Application ‘970 claims a method of treating infectious disease, chronic infectious disease, or chronic viral infections comprising the administration of a pharmaceutical composition to a subject in need of treatment (see claim 58).However, ‘970 does not claim that the cytokine is immunotherapeutic agent is IL-10
These deficiencies are taught by Naing.
Naing teaches IL-10 and PD-1 receptors are both expressed on activated and exhausted CD8+ T cells and that the cytokine IL-10 stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. Naing cites this rationale for combining AMO010 human IL-10 co-administered with an anti-PD-1 antibody (Background). Naing found that AMO010 plus nivolumab or pembrolizumab was well tolerated and responding patients had a higher degree of CD8+ T cell invigoration (Results).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art to modify the Il-7 linked invention of ‘970 by linking IL-10 as taught by Naing to the anti-PD-1 antibody of ‘970, to arrive at the instant invention. One would have been motivated to do so because covalently linking an immunotherapeutic agent to an anti-PD-1 antibody facilitates delivery of the immunotherapeutic agent directly to immune effector cells. One would have been motivated to specifically use IL-10 as the immunotherapeutic agent, as IL-10 is known in the art to stimulate cytotoxicity and proliferation in exhausted CD8+ T cells.
Claims 30-31 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 35-59 of Copending Application No. 17/414,970 in view of Naing (supra), as applied to claims 25-26, 29, 32, and 34-49 above, in view of Sharma (supra).
The disclosures/teachings of Application ‘970 and Naing are discussed above and are incorporated herein.
Regarding claims 30-31, Application ‘970 does not claim the anti-PD-1 antibody covalently linked to a human transmembrane immune protein of type I or II or a fragment thereof. As set forth above, the teachings of Sharma remedy this deficiency. Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have covalently linked the anti-PD-1 antibody of Application ‘970 to the immunotherapeutic agents as taught by Sharma, to arrive at the instant invention. One would have been motivated to do so because combination therapies that simultaneously target PD-1 and other inhibitory pathways or costimulatory molecules are known in the art, and are known to improve anti-tumor immune responses.
Claims 33 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 35-59 of Copending Application No. 17/414,970 in view of Linch (Front Oncol. 2015 Feb 16;5:34).
The disclosures/teachings of Patent ‘430 are discussed above and are incorporated herein.
Regarding claim 33, Application ‘970 does not disclose the immunotherapeutic agent is OX40L. This deficiency is taught by Linch who teaches that OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies (Abstract). Linch teaches that OX40L-Fc fusion proteins results in tumor regression in several preclinical models (Pg. 2, right column, full paragraph 1, Lines 1-4 and Table 1). Linch teaches OX40 agonism can complement PD-1 blockade by supporting the expansion, survival, and effector function of activated CD4 and CD8 T cells that express the PD-1 receptor (Pg. 7, Left column, full paragraph 2, Lines 1-9).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art to modify the anti-PD-1 antibody of Application ‘970 by covalently linking an OX40L therapeutic agent. One would be motivated to do so because Linch teaches OX40L administration results in tumor regression and suggest combination therapy with PD-1 blockage therapy to support the expansion, survival, and effector function of T cells.
Copending Application No. 17/785,427
Claims 25-26, 29, 32-33, 37, 39, 41, and 48-49 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25-48 of Copending Application No. 17/785,427 (reference application) in view of Niang (supra), as evidenced by Goodwin (PNAS 1989, 86 (1) 302-306). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Application ‘427 anticipate instant claims 25-29, 32, 37, 39, and 41.
This is a provisional nonstatutory double patenting rejection.
Regarding claims 25-26 and 32, Application ‘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 claim 29, Application ‘427 claims the bifunctional molecule comprising an IL-7 variant with at least 75% identity with wild-type IL-7 (see claim 25), which is known to have a molecular weight of 17.4 kDa, as evidenced by Goodwin (see abstract; reads on “wherein the immunotherapeutic agent fragment thereof has a size comprised between 10 kDa and 50 kDa” in instant claim 29).
Regarding claim 33, Application ‘427 claims the immunotherapeutic agent is CD80 (see ‘427 claim 33).
Regarding claim 37, Application ‘427 claims an isolated nucleic acid molecule or a group of isolated nucleic acid molecules encoding the bifunctional molecule (see claim 45).
Regarding claim 39, Application ‘427 claims a host cell comprising the isolated nucleic acid molecule (see claim 46).
Regarding claims 41, Application ‘427 claims a pharmaceutical composition comprising the bifunctional molecule and a pharmaceutically acceptable carrier (see claim 47).
However, ‘427 does not claim that the cytokine is immunotherapeutic agent is IL-10
These deficiencies are taught by Naing.
Naing teaches IL-10 and PD-1 receptors are expressed on activated and exhausted CD8+ T cells and that the cytokine IL-10 stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. Naing cites this rationale for combining AMO010 human IL-10 co-administered with an anti-PD-1 antibody (Background). Naing found that AMO010 plus nivolumab or pembrolizumab was well tolerated and responding patients had a higher degree of CD8+ T cell invigoration (Results).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art to modify the Il-7 linked invention of ‘427 by linking IL-10 as taught by Naing to the anti-PD-1 antibody of ‘427, to arrive at the instant invention. One would have been motivated to do so because covalently linking an immunotherapeutic agent to an anti-PD-1 antibody facilitates delivery of the immunotherapeutic agent directly to immune effector cells. One would have been motivated to specifically use IL-10 as the immunotherapeutic agent, as IL-10 is known in the art to stimulate cytotoxicity and proliferation in exhausted CD8+ T cells.
Claims 30-31 remain/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 Naing (supra), as applied to claims 25-26, 29, 32-33, 37, 39, 41, and 48-49 above, in view of Sharma (supra).
The disclosures/teachings of Application ‘427 and Sharma are discussed above and are
incorporated herein.
Regarding claims 30-31, Application ‘427 does not claim the anti-PD-1 antibody covalently linked to a human transmembrane immune protein of type I or II or a fragment thereof. As set forth above, the teachings of Sharma remedies this deficiency. Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have covalently linked the anti-PD-1 antibody of Application ‘427 to the immunotherapeutic agents as taught by Sharma, to arrive at the instant invention. One would have been motivated to do so because combination therapies that simultaneously target PD-1 and other inhibitory pathways or costimulatory molecules are known in the art, and are known to improve anti-tumor immune responses.
Claims 34-36, 38, 40, and 42-49 remain/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 Naing (supra), as applied to claims 25-26, 29, 32-33, 37, 39, 41, and 48-49 above, in view of Codarri Deak (supra).
The disclosures/teachings of Application ‘427 and Codarri Deak are discussed above and are incorporated herein.
Regarding claims 34-36, Application ‘427 claims the bifunctional molecule, wherein the binding moiety comprises: a heavy chain constant domain derived from a human IgG1 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P33 IS; E333A; S239D/A330L/1332E; P2571/Q311; K326W/E333S; S239D/1332E/G236A; N297A; L234A/L235A; N297A + M252Y/S254T/T256E; K322A; and K444A (see claim 46; reads on instant claims 34-35); and a heavy chain constant domain derived from a human IgG4 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P, L234A/L235A, S228P + M252Y/S254T/T256E and K444A (see claim 47; reads on instant claim 36; also reads on instant claim 34). However, Application ‘427 does not claim that the binding moiety comprises a light chain constant domain derived from a human kappa light chain constant domain.
Codarri Deak discloses that “the light chain of an immunoglobulin may be assigned to one of two types, called kappa (K) and lambda (A), based on the amino acid sequence of its constant domain” (see p. 19 lines 11-14). It would have been prima facie obvious to develop the binding moiety to comprise a light chain constant domain derived from a human kappa light chain constant domain, to arrive at the present invention, as it is well known in the art, and Codarri Deak teaches a finite number of identified, predictable immunoglobulin light chain types (kappa or lambda), with a reasonable expectation of success. (See MPEP § 2143).
Regarding claims 38 and 40, Application ‘427 does not specifically claim a vector or the method for producing the bifunctional molecule. However, Codarri Deak discloses a vector comprising the polynucleotide(s) encoding the claimed immunoconjugate (see claim 25; reads on instant claim 38), as well as a method for producing the immunoconjugate comprising a step of culturing the host cell and optionally a step of recovering the immunoconjugate (see claim 27; reads on instant claim 40). Therefore, it would have been prima facie obvious to develop the vector and method described, to arrive at the present invention, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. (See MPEP § 2143).
Regarding claims 42 and 45, Application ‘427 does not claim the pharmaceutical composition administered in combination with additional therapeutic agent(s). As set forth above, the teachings of Codarri Deak remedies this deficiency (see p. 69 lines 15-27). Therefore, it would have been prima facie obvious to have administered the claim the pharmaceutical composition in combination with additional therapeutic agent(s), as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. (See MPEP § 2143).
Regarding claims 43-44 and 46-47, Application ‘427 claims a method of treating cancer or an infectious disease comprising the administration of the pharmaceutical composition to a subject having cancer or an infectious disease (see claim 48), but does not specify the cancer or infectious disease type.
As set forth above, it would have been prima facie obvious to one of ordinary skill in the art to have developed the method of the current invention by treating disease, wherein the disease is a chronic viral infections, as the teachings of Codarri Deak suggest combining an antibody against PD-1 and the immunotherapeutic agent, IL-2, results in expansion of virus-specific T cells, and thus, may be beneficial for treating chronic viral infections, such as HIV and HSV (see p. 92-93; reads on instant claims 46-47).
Codarri Deak further teaches the method of treating cancer, wherein the cancer is kidney cancer, skin cancer, lung cancer, colorectal cancer, breast cancer, brain cancer, head and neck cancer, prostate cancer and bladder cancer (see claims 31-36 and p. 66 lines 7-10; reads on instant claims 43-44). It would have been prima facie obvious to have developed the method of treating cancer, particularly the cancers listed above, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. (See MPEP § 2143).
Pat. No. 12,331,118 (formerly Copending Application No. 17/830,381)
Claims 25, 29, 32, and 34-49 remain/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Pat. No. 12,331,118 in view of Codarri Deak (supra) and Naing (supra).
Regarding claims 25, 32, 41, and 48-49 Patent ’118 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)
Patent ‘118 further claims composition administered in combination with an additional therapeutic (see claim 8). However, Patent ‘118 does not claim that the antibody is covalently linked to an immunotherapeutic agent or fragment.
As set forth above, Codarri Deak discloses an immunoconjugate comprising an antibody that binds to PD-1 and an IL-2 polypeptide (see claim 1, reads on instant claims 25, 28 and 32-33), wherein the C-terminal end of the antibody is covalently linked to the N-terminal end of the immunotherapeutic agent through a peptide linker (see p. 8 lines 10-13). Codarri Deak further discloses the benefits of using IL-2 for treating (see p. 2 lines 16-19; p. 5; p. 6 lines 1-2). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have covalently linked an immunotherapeutic agent, such as IL-2, as taught by Codarri Deak, to the anti-PD-1 antibody of Application ‘381, to arrive at the instant invention. One would have been motivated to do so because covalently linking an immunotherapeutic agent to an anti-PD-1 antibody facilitates delivery of the immunotherapeutic agent directly to immune effector cells. One would have been motivated to specifically use IL-2 as the immunotherapeutic agent, as IL-2 is known in the art to be an attractive immunotherapy for metastatic cancers due to its ability to expand and increase the effector functions of lymphocyte populations in vivo.
Regarding claims 29, Codarri Deak discloses that IL-2 is 15.5 kDa (see p. 1 line 10; reads on “wherein the immunotherapeutic agent fragment thereof has a size comprised between 10 kDa and 50 kDa” in instant claim 29).
Regarding claims 34, Patent ‘118 claims the antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment thereof 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 IgG1, IgG2, IgG3 or IgG4 heavy chain constant domain (see claim 3; reads on instant claim 34 in its entirety).
Regarding claims 35, Patent ‘118 claims the antibody or antigen-binding fragment, wherein the antibody or antigen binding fragment thereof 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 IgG1 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of T250Q/M428L; M252Y/S254T/T256E + H433K/N434F; E233P/L234V/L235A/G236A + A327G/A330S/P33 IS; E333A; S239D/A330L/1332E; P2571/Q311; K326W/E333S; S239D/1332E/G236A; N297A; L234A/L235A; N297A + M252Y/S254T/T256E; K322A; and K444A (see claim 4; reads on instant claim 35 in its entirety).
Regarding claims 36, Patent ‘118 claims the antibody or antigen-binding fragment, wherein the antibody or antigen binding fragment thereof 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 IgG4 heavy chain constant domain, optionally with a substitution or a combination of substitutions selected from the group consisting of S228P, L234A/L235A, S228P + M252Y/S254T/T256E and K444A (see claim 5; reads on instant claim 36 in its entirety).
Regarding claims 37-40, Patent ‘118 does not claim a method of making the immunoconjugate or the antibody, using nucleic acids, vectors, or host cells. Codarri Deak discloses: an isolated polynucleotide encoding the immunoconjugate; a vector comprising said polynucleotide; a host cell comprising said polynucleotide or vector; and a method of producing the immunoconjugate and optionally recovering said immunoconjugate (see claims 24-27; reads on instant claims 37-40). Therefore, it would have been prima facie obvious to develop the polynucleotide, vector, host cell, and method described, to arrive at the present invention, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. (See MPEP § 2143).
Regarding claims 42 and 45, Patent ‘118 claims the antibody, antigen binding fragment or composition administered in combination with a radiotherapy or an additional therapeutic (see claim 8; reads on instant claim 45), however does not claim the therapeutics listed in instant claims 42. Codarri Deak discloses that the immunoconjugates according to the invention may be administered in combination with one or more additional therapeutic agents, such as an immunomodulatory agent, a cytostatic agent, an inhibitor of cell adhesion, a cytotoxic agent, an activator of cell apoptosis, an agent that increases the sensitivity of cells to apoptotic inducers, a microtubule disruptor, an antimetabolite, a topoisomerase inhibitor, a DNA intercalator, an alkylating agent, a hormonal therapy, a kinase inhibitor, a receptor antagonist, an activator of tumor cell apoptosis, or an antiangiogenic agent (see p. 69 lines 15-27; reads on instant claims 42 and 45). Therefore, it would have been prima facie obvious to have administered the immunoconjugate in combination with an additional therapeutic, to arrive at the present invention, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. (See MPEP § 2143).
Regarding claims 43-44, Patent ‘118 claims a method of treating cancer in a subject comprising administering the composition, wherein the cancer is malignant mesothelioma, colorectal cancer and hepatocellular carcinoma (see claim 6; reads on instant claims 43-44).
Regarding claims 46-47, Patent ‘118 does not claim treating (chronic) infectious disease or chronic viral infections. As set forth above, it would have been prima facie obvious to one of ordinary skill in the art to have developed the method of the current invention by treating disease, wherein the disease is a chronic viral infections, as the teachings of Codarri Deak suggest combining an antibody against PD-1 and the immunotherapeutic agent, IL-2, results in expansion of virus-specific T cells, and thus, may be beneficial for treating chronic viral infections, such as HIV and HSV (see p. 92-93; reads on instant claims 46-47).
However, Patent ‘118 does not claim that the cytokine is immunotherapeutic agent is IL-10
These deficiencies are taught by Naing.
Naing teaches IL-10 and PD-1 receptors are expressed on activated and exhausted CD8+ T cells and that the cytokine IL-10 stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. Naing cites this rationale for combining AMO010 human IL-10 co-administered with an anti-PD-1 antibody (Background). Naing found that AMO010 plus nivolumab or pembrolizumab was well tolerated and responding patients had a higher degree of CD8+ T cell invigoration (Results).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art to modify the Il-7 linked invention of ‘118 by linking IL-10 as taught by Naing to the anti-PD-1 antibody of ‘118, to arrive at the instant invention. One would have been motivated to do so because covalently linking an immunotherapeutic agent to an anti-PD-1 antibody facilitates delivery of the immunotherapeutic agent directly to immune effector cells. One would have been motivated to specifically use IL-10 as the immunotherapeutic agent, as IL-10 is known in the art to stimulate cytotoxicity and proliferation in exhausted CD8+ T cells.
Claims 30-31 remain/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Pat. No. 12,331,118 in view of Codarri Deak (supra) and Naing (supra), as applied to claims 25, 27-29 and 32-47 above, in view of Sharma (supra).
The disclosures/teachings of Patent ‘118 and Sharma are discussed above and are
incorporated herein.
Regarding claims 30-31, Patent ‘118 does not claim the anti-PD-1 antibody covalently linked to a human transmembrane immune protein of type I or II or a fragment thereof. As set forth above, the teachings of Sharma remedies this deficiency. Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have covalently linked the anti-PD-1 antibody of Application ‘381 to the immunotherapeutic agents as taught by Sharma, to arrive at the instant invention. One would have been motivated to do so because combination therapies that simultaneously target PD-1 and other inhibitory pathways or costimulatory molecules are known in the art, and are known to improve anti-tumor immune responses.
Claims 33 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Pat. No. 12,331,118 in view of Linch (Front Oncol. 2015 Feb 16;5:34).The disclosures/teachings of Patent ‘430 are discussed above and are incorporated herein.
Regarding claim 33, Patent ‘118 does not disclose the immunotherapeutic agent is OX40L. This deficiency is taught by Linch who teaches that OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies (Abstract). Linch teaches that OX40L-Fc fusion proteins results in tumor regression in several preclinical models (Pg. 2, right column, full paragraph 1, Lines 1-4 and Table 1). Linch teaches OX40 agonism can complement PD-1 blockade by supporting the expansion, survival, and effector function of activated CD4 and CD8 T cells that express the PD-1 receptor (Pg. 7, Left column, full paragraph 2, Lines 1-9).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art to modify the anti-PD-1 antibody of Patent ‘118 by covalently linking an OX40L therapeutic agent. One would be motivated to do so because Linch teaches OX40L administration results in tumor regression and suggest combination therapy with PD-1 blockage therapy to support the expansion, survival, and effector function of T cells.
Copending Application No. 18/285,659:
Claims 25, 29, 32, 37, 39, 41, and 48-49 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-32 of Copending Application No. 18/285,659 (reference application), as evidenced by Codarri Deak (supra) and Naing (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Application ‘659 anticipate the instant claims above.
This is a provisional nonstatutory double patenting rejection.
Regarding claims 25 and 48-49, Application ‘659 claims a bifunctional molecule comprising: an antigen-binding fragment that binds to PD-1 (see claims 17 and 26-27); and an immuno-stimulating cytokine, wherein the N-terminal end of the immuno-stimulating cytokine is covalently linked to the C-terminal end of the light chain of said antigen binding fragment. Application ‘659 further claims the sequences below, wherein the following SEQ ID NOs of Application ‘659 share 100% identity with the following instant SEQ ID NOs (see claim 27):
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)
Regarding claim 29 and 32, Application ‘659 claims the bifunctional molecule, wherein the immuno-stimulating cytokine is: IL-2 (IL being interleukin), IL-4, IL-5, IL-6, IL-12A, IL-12B, IL-13; IL-15, IL-18, IL-21, IL-23, IL- 24; IFNa, IFNB, BAFF, LTa, and LTB, or a variant thereof having at least 80 % of identity with the wildtype protein (see claim 17 and 20-21; reads on instant claim 32-33), where IL-2 is known to have a molecular weight of 15.5 kDa as evidenced by Codarri Deak, as set forth above (reads on instant claim 29).
Regarding claims 37, Application ‘659 claims an isolated nucleic acid molecule or a group of isolated nucleic acid molecules encoding the bifunctional molecule (see claim 28).
Regarding claims 39, Application ‘659 claims a host cell comprising the isolated nucleic acid molecule (see claim 29).
Regarding claims 41, Application ‘659 claims a pharmaceutical composition comprising the bifunctional molecule and a pharmaceutically acceptable carrier (see claim 30).
Claims 30-31 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-32 of Copending Application No. 18/285,659, as applied to claims 25, 29, 32, 37, 39, 41, and 48-49 above, in view of Sharma (supra).
The disclosures/teachings of Application ‘659 and Sharma are discussed above and are
incorporated herein.
Regarding claims 30-31, Application ‘659 does not claim the anti-PD-1 antibody covalently linked to a human transmembrane immune protein of type I or II or a fragment thereof. As set forth above, the teachings of Sharma remedies this deficiency. Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have covalently linked the anti-PD-1 antibody of Application ‘659 to the immunotherapeutic agents as taught by Sharma, to arrive at the instant invention. One would have been motivated to do so because combination therapies that simultaneously target PD-1 and other inhibitory pathways or costimulatory molecules are known in the art, and are known to improve anti-tumor immune responses.
Claims 34-36, 38, 40, and 42-49 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-32 of Copending Application No. 18/285,659, as applied to claims 25, 29, 32, 37, 39, 41, and 48-49 above, in view of Codarri Deak (supra) and Naing (supra).
The disclosures/teachings of Application ‘659 and CODARRI DEAK are discussed above and are incorporated herein.
Regarding claims 34-36, Application ‘659 does not claim the bifunctional molecule, wherein the antibody or antigen binding fragment thereof 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 IgG1 heavy chain constant domain, with the substitution(s) listed in instant claim 35. As set forth above, Codarri Deak discloses that the light chain may be assigned to kappa or lambda (see p. 19 lines 11-14). It would have been prima facie obvious to develop the binding moiety to comprise a light chain constant domain derived from a human kappa light chain constant domain, to arrive at the present invention, as it is well known in the art, and Codarri Deak teaches a finite number of identified, predictable immunoglobulin light chain types (kappa or lambda), with a reasonable expectation of success. (See MPEP § 2143). Codarri Deak further discloses IgG1 and IgG4 subtypes (see p. 19 lines 9-11), as well as the following mutations associated with said subtypes: L234A/L235A and S228P respectively (see p. 45 lines 26-27; p. 46 lines 21-22). It would have been prima facie obvious to develop the binding moiety to comprise a heavy chain constant domain derived from IgG1 or IgG4, with mutations L234A/L235A or S228P, as these antibody subtypes and associated mutations are well known in the art, and doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. (See MPEP § 2143).
Regarding claims 38 and 40, Application ‘659 does not specifically claim a vector or the method for producing the bifunctional molecule. As set forth above, Codarri Deak remedies this deficiency (see claim 25, reads on instant claim 38; see claim 27, reads on instant claim 40). Therefore, it would have been prima facie obvious to develop the vector and method described, to arrive at the present invention, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. (See MPEP § 2143).
Regarding claims 42 and 45, Application ‘659 does not claim the pharmaceutical composition administered in combination with additional therapeutic agent(s). As set forth above, the teachings of Codarri Deak remedies this deficiency (see p. 69 lines 15-27). Therefore, it would have been prima facie obvious to have administered the claim the pharmaceutical composition in combination with additional therapeutic agent(s), as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. (See MPEP § 2143).
Regarding claims 43-44 and 46-47, Application ‘659 claims a method of treating cancer or an infectious disease comprising the administration of the pharmaceutical composition to a subject having cancer or an infectious disease (see claim 31), but does not specify the cancer or infectious disease type.
As set forth above, it would have been prima facie obvious to one of ordinary skill in the art to have developed the method of the current invention by treating disease, wherein the disease is a chronic viral infections, as the teachings of Codarri Deak suggest combining an antibody against PD-1 and the immunotherapeutic agent, IL-2, results in expansion of virus-specific T cells, and thus, may be beneficial for treating chronic viral infections, such as HIV and HSV (see p. 92-93; reads on instant claims 46-47).
Codarri Deak further teaches the method of treating cancer, wherein the cancer is kidney cancer, skin cancer, lung cancer, colorectal cancer, breast cancer, brain cancer, head and neck cancer, prostate cancer and bladder cancer (see claims 31-36 and p. 66 lines 7-10; reads on instant claims 43-44). It would have been prima facie obvious to have developed the method of treating cancer, particularly the cancers listed above, as doing so amounts to no more than combining prior art elements according to known methods to yield predictable results. (See MPEP § 2143).
Claims 33 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-32 of Copending Application No. 18/285,659 in view of Linch (Front Oncol. 2015 Feb 16;5:34).The disclosures/teachings of Patent ‘430 are discussed above and are incorporated herein.
Regarding claim 33, Application ‘659 does not disclose the immunotherapeutic agent is OX40L. This deficiency is taught by Linch who teaches that OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies (Abstract). Linch teaches that OX40L-Fc fusion proteins results in tumor regression in several preclinical models (Pg. 2, right column, full paragraph 1, Lines 1-4 and Table 1). Linch teaches OX40 agonism can complement PD-1 blockade by supporting the expansion, survival, and effector function of activated CD4 and CD8 T cells that express the PD-1 receptor (Pg. 7, Left column, full paragraph 2, Lines 1-9).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art to modify the anti-PD-1 antibody of Application ‘659 by covalently linking an OX40L therapeutic agent. One would be motivated to do so because Linch teaches OX40L administration results in tumor regression and suggest combination therapy with PD-1 blockage therapy to support the expansion, survival, and effector function of T cells.
Additional Provisional Nonstatutory Double Patenting Rejections:
The disclosures/teachings of the following are discussed above and are incorporated herein: Codarri Deak, Naing Sharma, Goodwin.
The following is/are rejected for similar reasons as discussed in the provisional nonstatutory double patenting rejections above.
Copending Application No. 17/414,971:
(See rejections over Application ‘970 above in particular)
Claims 25-26, 30, 32-33, and 34-49 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-43 of Copending Application No. 17/414,971 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the bifunctional molecule comprising an anti-PD-1 antibody and SIRPa of Application ‘971 anticipates the instant claims listed above. SEQ ID NOs: 1-3, 12, 15-17, and 26 of Application ‘971, as claimed (see claims 27-28), anticipate instant CDRs set forth in SEQ ID NOs: 1, 2, 5, 8, 10, 14, 15, and 16. SEQ ID NOs: 17 and 26 anticipate instant VH set forth in instant SEQ ID NO: 19, 22 and 24 and instant VL set forth in SEQ ID NO:28. The bifunctional molecules comprises a human SIRPa or fragment thereof.
Claim 30 remains provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-43 of Copending Application No. 17/414,971, as applied to claims 25-26, 30, 32-33, and 34-49 above, in view of Sharma (supra).
Claims 29 and 32 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-43 of Copending Application No. 17/414,971, as applied to 25-26, 30, 32-33, and 34-49 above, in view of CODARRI DEAK (supra).Claim 33 is provisionally rejection provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-43 of Copending Application No. 17/414,971, as applied to claims 25-26, 30, 32-33, and 34-49 above in view of Linch (supra).
Copending Application No. 18/267,795:
(See rejections over Application ‘970 above in particular)
Claims 25-26, 29, 32, and 34-49 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-68 of Copending Application No. 18/267,795 (reference application), in view of Codarri Deak (supra) and Naing (supra) as evidenced by Goodwin (PNAS 1989, 86 (1) 302-306). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Application ‘795 anticipate the instant claims listed above. The following SEQ ID NOs of Application ‘795 share 100% identity with the following instant SEQ ID NOs (see claim 56):
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
Claims 30-31 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-68 of Copending Application No. 18/267,795, as applied to claims 25-26, 29, 32, and 34-49 above, in view of Sharma (supra).
Claim 33 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-68 of Copending Application No. 18/267,795, as applied to claims 25-26, 29, 32, and 34-49 above, in view of Linch (supra).
Copending Application No. 18/285,664:
(See rejections over Application ‘659 above in particular)
Claims 25, 33, 37, 39, and 41, and 48-49 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-32 of Copending Application No. 18/285,664 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Application ‘664 anticipate the instant claims listed above. The bifunctional molecule comprises a human SIRPa or fragment thereof and the following SEQ ID NOs of Application ‘664 share 100% identity with the following instant SEQ ID NOs (see claim 26):
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)
Claims 30-31 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-32 of Copending Application No. 18/285,664, as applied to claims 25, 33, 37, 39, and 41, and 48-49 above, in view of Sharma (supra).
Claims 29, 32-36, 38, 40, and 42-47 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-32 of Copending Application No. 18/285,664, as applied to claims 25, 33, 37, 39, and 41, and 48-49 above, in view of Codarri Deak (supra) and Naing (supra).
Response to Applicant’s Remarks
Applicant's arguments filed 11/06/2025 have been fully considered but they are not persuasive.
The applicant argues the claimed bifunctional molecules comprise particular classes of immunotherapeutic agents that exhibit surprising and unexpected properties. The applicant further states: “The Example section of the pending application demonstrates the improved properties of the claimed bifunctional molecules in terms of manufacturability and productivity (see Example I and Figures 1-3). As discussed in the previously submitted Morello Declaration, the addition of an immunotherapeutic agent (such as CD80, 4-IBBL, OX40L, or CD86) would have been expected to at least slightly decrease the productivity (mean yield) of the fusion protein; however, this is not the case.” (Remarks, Pg. 10)
The applicant concludes, “the Example section of the pending application shows that the claimed bifunctional molecules increase T cell proliferation and activation ex vivo, at least as much, if not more, than an anti-PD-1 antibody alone (see Example 2 and Figures 10 and 11 of the PCT application). Such properties would not have been expected in light of the claims of the '430 patent, alone, or in combination with Codarri Deak et al. Indeed, it is very challenging to predict the effect of an immunotherapeutic agent's fusion with an antibody, whether on its production or antigen binding capabilities or on its biological properties.” (Remarks, Pg. 11)
In response, the applicant's argument of unexpected results is directed to a feature that is not recited in the rejected claims. The assertion that it is unexpected that bifunctional antibody would have mean production yields equivalent to that of a conventional monoclonal antibody does not have any support in the claims, which define the general structure of the bifunctional molecule and identify the anti-PD-1 binding domain. The challenges of producing a bispecific antibody notwithstanding, the use of the specific antibody variable regions as disclosed in the patents and copending applications as part of a fusion protein is still obvious.
Conjugation of cytokines to antibodies is known in the prior art. For example, Neri (Curr Opin Immunol. 2016 Jun;40:96-102) teaches IgG-based immunocytokines with a cytokine moiety at the C-terminal end of the heavy or light chain (Fig. 1, a &b). Neri also discloses immunocytokines with IL-2, IL-12 and TNF moieties (Table 1).
Pertaining to anti-PD-1 antibody conjugates specifically, US2020/0048351A1 teaches anti-PD-1 antibody conjugated to TGFbRII, , one of the claimed immunotherapeutic agents of the instant invention. Therefore, conjugation of immunotherapeutic agents to a PD-1 antibody is known in the art, and addition of a therapeutic agent to the specific anti-PD-1 antibody of the instant invention is obvious.
The applicant argues that it is challenging to predict the effect of an immunotherapeutic agent’s fusion with an antibody on its production or antigen binding capabilities or on its biological properties. To this end, claim 25 is directed to 97 different putative immunotherapeutics and the reported unexpected results cited in the applicant’s remarks could not reasonably be extrapolated to all 97 agents. The novelty of the instant invention is therefore directed to the novel PD-1 antibody and not conjugation to one of 97 claimed agents.
For these reasons, the nonstatutory double patenting rejections over Pat. Nos. 11,352,430 and 12,331,118 and co-pending applications 17/414,970, 17/414,971, 17/785,427, 18/267,795, 18/285,659, 18/285,664 are maintained herein.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646