DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Amendment
2. The amendment of April 13, 2026 has been entered. Claim 34 has been amended. Claim 42 has been newly added. Claims 2, 4-5, 8-18, 20-29 and 38 have been cancelled. Claims 1, 3, 6-7, 19, 30-37 and 39-42 are under consideration in this Office Action.
Maintained Claim Objections
3. Claim 34 is objected to because of the following informalities: Claim 34 is drawn to anti-PD-1 antibodies, however STI-1110 and MPDL3280A are traditionally known as an anti-PD-L1 antibodies. Appropriate correction is required.
Response to Arguments
4. Applicant's arguments filed April 13, 2026 have been fully considered but they are not persuasive. Applicants amended claim 34 to recite “STI-1110” and “MPDL3280A”, which are traditionally known as anti-PD-L1 antibodies. Applicants amendment did not exclude the PD-L1 antibodies listed by claim 34 which are limited to only PD-1 antibodies.
STI-1110 (also referred to as STI-A1110) is a fully human anti-PD-1 monoclonal antibody discovered by Sorrento Therapeutics using their proprietary G-MAB library platform, targeting hematological and solid tumor cancers. See STI-A1110 - Drug Targets, Indications, Patents - Synapse
MPDL3280A is the developmental code name for the humanized, engineered monoclonal antibody Atezolizumab (sold under the brand name Tecentriq). It is an immune checkpoint inhibitor that targets Programmed Death-Ligand 1 (PD-L1), blocking it from binding to the PD-1 and B7.1 receptors. See Development of MPDL3280A, an Anti-PD-L1 Antibody Engineered for Enhanced Efficacy and Safety - Annals of Oncology
Therefore, Applicants amendment does not overcome the claim objection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
5. Claims 1, 3, 19, 30-31, 33-35, 39 and 40-42 are rejected under 35 U.S.C. 103 as being unpatentable over Linnebacher (DE102008045815 published March 2010; priority to Sept. 2008) and in view of Korman et al., (US Patent Publication 2009/0217401 published Aug. 2009). It is noted that Linnebacher is available on Google patents.
The claims are drawn to a method of treating cancer in a human subject comprising co-administering to the subject an effective amount of (1) an immune checkpoint inhibitor wherein the immune checkpoint inhibitor is an antibody, and (2) a bacterial formulation comprising bacteria of the genus Bifidobacterium, wherein the bacterial formulation comprises bacteria selected from the group consisting of Bifidobacterium animalis and Bifidobacterium breve, wherein the bacterial formulation enhances an anti-cancer immune response by the immune checkpoint inhibitor.
Linnebacher disclose combination of at least one antibody and a bacterium, which expresses Fc-receptors or proteins, which bind the light chain of an antibody, useful for the treatment of tumors and carcinomas [title]. Of the antitumoral effect is based on a combination of nonspecific, congenital and adaptive immune responses that differ in different ways shaping partly against the bacterial structures, but sometimes also directed against tumor structures. In this way, besides solid tumors also succeeded in micrometastasis and residual tumor cells be attacked [Description]. Particularly preferred are immunoglobulin M or G, with immunoglobulin G highest (Ig G) is preferred. The immunoglobulin G is preferably selected from the group of G1, G2a, G2b, G3a, G3b or Gb4. As already explained above, the invention also relates to combinations of at least one antibody and a bacterium containing proteins that bind the light chain of an antibody, which expresses the at least one antibody via its light chain.. [Description]. All in all it is preferred that the at least one antibody is cetuximab, panitumumab or trastuzumab [Description]. The cancers whose growth may be inhibited using the antibodies of the invention include cancers typically responsive to immunotherapy. Non-limiting examples of preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma). The bacterium is preferably selected from the group including Bifidobacterium breve [Description]. The use is also the combination according to the invention for the preparation of an agent for the treatment of tumors and their Precursors within the scope of the invention [Description]. For the treatment of tumors from the group of carcinomas. The use of the combination according to the invention for the preparation of an agent for the treatment of tumors from this group and their precursors is therefore likewise an object of the invention [Description]. Therefore the carcinomas are solid tumors; thereby teaching claim 39. The administration of the combination of at least one antibody and a bacterium for the treatment of tumors or their precursors preferably by intravenous, oral or intratumoral administration, being the intravenous Administration is particularly preferred [Description]. Thus teaching claims 6 and 19. Therefore Linnebacher., teach a method of treating cancer in a human subject comprising co-administering to the subject an antibody and Bifidobacterium breve. However, Linnebacher do not teach the anti-cancer antibodies are also known as an immune checkpoint inhibitor antibodies such as anti-PD-1, anti- PD-L1 or anti-CTLA-4.
Korman et al., teach methods for treating cancer, using anti-PD-1 antibodies. The methods provide for using a combination immunotherapy, such as the combination of anti-CTLA-4 and anti-PD-1 antibodies, to treat hyperproliferative disease, such as cancer [abstract]. The antibodies of the invention can be, for example, full-length antibodies, for example of an IgG1 or IgG4 isotype [para 128]. The light chain constant region can be a kappa or lambda constant region, but most preferably is a kappa constant region [para 392]. The heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most preferably is an IgG1 or IgG4 constant region [para 391]. Korman et al., teach the use of anti-PD-1 antibodies and the use of combination immunotherapy, including the combination of anti-CTLA-4 and anti-PD-1 antibodies to treat cancer [para. 0001]. The method of inhibiting growth of tumor cells in a subject, comprising administering to a subject a therapeutically effective amount of an anti-PD-1 antibody, [para. 0133]. The “subject” includes any human [page 232]. Cancers whose growth may be inhibited using the antibodies of the invention include cancers typically responsive to immunotherapy. Non-limiting examples of preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), adenocarcinomas and other carcinoma types [para 469-470]. The present invention is also useful for treatment of metastatic cancers, especially metastatic cancers that express PD-L1 [para. 470].
Korman et al., commercially available anti-PD-1 antibodies [para. 130]; thereby teaching claim 33 and 41. Figure 30 shows anti-CTLA-4 antibody and anti-PD-1; thereby teaching claims 31 and 35. The anti-PD-1 antibodies include human monoclonal antibodies 17D8, 2D3, 4H1, 5C4, 4A11, 7D3 and 5F4 [para. 247]. It is noted that 5C4 is also known as Nivolumab, "OPDIV00"; formerly designated 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor Ab that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of antitumor T-cell functions (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9):846-56). Therefore Korman et al., claims 30 and 34. The treatment of a cancer tumor may include an anti-cancer antibody in combination with anti-PD-1 and anti-CTLA-4 antibodies, concurrently or sequentially or any combination thereof, which may potentiate an anti-tumor immune responses by the host [para 513]. Compositions comprising an antibody, or antigen-binding portion thereof, or immunoconjugate or bispecific molecule of the invention, and a pharmaceutically acceptable carrier, are also provided [para. 0130]. The antibodies of the invention exhibit one or more desirable functional properties, such as high affinity binding to PD-1, the ability to stimulate T cell proliferation, IFN-γ and/or IL-2 secretion in mixed lymphocyte reactions, the ability to inhibit binding of one or more PD-1 ligands (e.g., PD-L1 and/or PD-L2), and the ability to stimulate antibody responses and/or the ability to inhibit growth of tumor cells in vivo [para. 202]; thereby teaching claim 41. The examination of T cell subsets indicates that PD-1 is expressed on CD4 and CD8 memory and effector T cells, but absent on naïve CD4 or CD8 T cells [para 618]. Preferred routes of administration for antibodies of the invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration [para 458]. Thus teaching claim 19.
Therefore, it would have been prima facie obvious at the time of applicants’ invention to incorporate Korman et al., anti-PD-1 antibodies (anti-cancer antibodies) which are immune checkpoint inhibitors already known to treat solid tumors and melanomas into Linnebacher et al., method of treating cancer in a human subject comprising administering to the subject an anti-cancer antibody and a bacterial formulation when Linnebacher et al., already it was known to treat cancer in a human subject comprising administering to the subject bacterial formulations in combination with other anti-cancer antibody therapies to treat cancer. One of ordinary skill in the art would have a reasonable expectation of success by combining both components because the prior art teach combination therapy was well known to produce beneficial cancer treating results by interfering with PD-1 and reducing PD-1 expression and using bacteria to treat the site of carcinoma proliferation.
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take a method of treating cancer when each ingredient is well-known to treat cancer, and where there is no change in the respective function of immune check point inhibitor or the bacteria thus the combination would have yielded a reasonable expectation or success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
6. Applicant's arguments filed April 13, 2026 have been fully considered but they are not persuasive.
The rejection of claims 1, 3, 19, 30-31, 33-35, 39 and 40-42 under 35 U.S.C. 103 as being unpatentable over Linnebacher and in view of Korman et al., is maintained for reasons of record.
Applicants point to the claim recitation of “…the bacterial formulation enhances an anti-cancer immune response by the immune checkpoint inhibitor.” with the argument that the Office action does not teach this effect. However Applicants attention is directed to Linnebacher et al., which teach cancers growth may be inhibited using the antibodies in combination with Bifidobacterium breve. Korman et al., teach creating a combination immunotherapy, with the combination of anti-CTLA-4 and anti-PD-1 antibodies. Korman et al., teach functional properties, such as high affinity binding to PD-1, the ability to stimulate T cell proliferation, IFN-γ and/or IL-2 secretion in mixed lymphocyte reactions, the ability to inhibit binding of one or more PD-1 ligands (e.g., PD-L1 and/or PD-L2), and the ability to stimulate antibody responses and/or the ability to inhibit growth of tumor such as high affinity binding to PD-1, to stimulate T cell proliferation, IFN-γ and/or IL-2 secretion, and the ability to stimulate antibody responses and/or the ability to inhibit growth of tumor cells.
Applicants Position 1 argues that immune checkpoint inhibitors (ICIs) work by blocking checkpoint proteins from binding with their partner proteins, thereby enhancing the immune response. Applicants demonstrated through multiple different non-prior art sources that Bifidobacterium animalis and Bifidobacterium breve have an anti- inflammatory response. The art clearly teach the combination of immune checkpoint inhibitor antibody, and a bacterial formulation comprising bacteria of the genus Bifidobacterium.
As to Applicants’ argument on Position 2; there is no reason to argue about references not apart of the instant rejection. In this case, the issue is whether the prior art rejection teaches the instantly recited limitations. Here, the Office maintains that one of ordinary skill in the art would follow the teaching of Linnebacher in view of Korman et al., to achieve a method of treating cancer in a human subject comprising co-administering to the subject an effective amount of (1) an immune checkpoint inhibitor wherein the immune checkpoint inhibitor is an antibody, and (2) a bacterial formulation comprising bacteria of the genus Bifidobacterium, wherein the bacterial formulation comprises bacteria selected from the group consisting of Bifidobacterium animalis and Bifidobacterium breve, wherein the bacterial formulation enhances an anti-cancer immune response by the immune checkpoint inhibitor. Moreover, the Office presented numerous benefits and advantages taught by Korman et al., which would teach, suggest, and/or motivate one of ordinary skill in the art to incorporate the teaching of Korman et al.
Linnebacher., teach a method of treating cancer in a human subject comprising co-administering to the subject an anti-cancer IgG antibody and Bifidobacterium breve. The administration of the combination of at least one antibody and a bacterium for the treatment of tumors or their precursors preferably by intravenous, oral or intratumoral administration [Description].Thus, one of ordinary skill would obviously know to co-administer an anti-cancer antibody and a bacterium for the treatment of tumors. The only is that Linnebacher et al., did not further define anti-cancer antibodies. Korman et al., clearly teach anti-cancer antibodies for the treatment of tumors. Korman et al., also teach IgG antibodies. Additionally, Korman et al., teach anti-PD-1 antibodies are well known to treat the same types of cancers and tumors. Furthermore, the combination of familiar elements, anti-cancer antibodies and B. breve taught by Linnebacher et al., and ICI anti-PD-1 antibodies as taught y Korman et al., to be co-administered according to known methods taught by Linnebacher is likely to be obvious when it does no more than yield predictable results of treating cancers and tumors. In order to rely on equivalence as a rationale supporting an obviousness rejection, the equivalency must be recognized in the prior art, and cannot be based on applicant’s disclosure or the mere fact that the components at issue are functional or mechanical equivalents. In re Ruff, 256 F.2d 590, 118 USPQ 340 (CCPA 1958) (The mere fact that components are claimed as members of a Markush group cannot be relied upon to establish the equivalency of these components. However, an applicant’s expressed recognition of an art-recognized or obvious equivalent may be used to refute an argument that such equivalency does not exist.); Smith v. Hayashi, 209 USPQ 754 (Bd. of Pat. Inter. 1980) (The mere fact that phthalocyanine and selenium function as equivalent photoconductors in the claimed environment was not sufficient to establish that one would have been obvious over the other. However, there was evidence that both phthalocyanine and selenium were known photoconductors in the art of electrophotography. "This, in our view, presents strong evidence of obviousness in substituting one for the other in an electrophotographic environment as a photoconductor." 209 USPQ at 759.).
An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). In this case, the prior Linnebacher et al., teach the inclusion of anti-cancer antibodies. Korman et al., teach the anti-PD-1 antibodies are anti-cancer antibodies. Linnebacher et al., teach the co-administration of a formulation to treat cancer. Korman et al., teach the anti-PD-1 antibodies treat cancer. Therefore, the prior art evidences the antibodies equivalence as anti-cancer antibodies that treat cancer and tumours. This, presents strong evidence of obviousness in substituting one anti-cancer antibody for the other anti-cancer anti-PD-1 antibody in the treatment of cancer. Accordingly, this argument is not persuasive.
Claim Rejections - 35 USC § 103
7. Claims 1, 3, 6-7, 19, 30-31, 33-35, 39 and 40-41 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Stritzker et al., (US Patent Pub. 2008/0193373 published August 2008; priority to July 2007) in view of Korman et al., (US Patent Publication 2009/0217401 published Aug. 2009).
Stritzker et al., teach methods which use microorganisms for treating a disease, disorder or condition. Such diseases and disorders include sites of cell proliferation, proliferative conditions, neoplasms, tumors and neoplastic diseases [abstract]. The methods can be used on humans [para. 036]. Stritzker et al., uses of microorganisms or cells in the methods for treating a site of proliferation or a proliferative condition, such as a tumor, tumor tissue, cancer or metastasis [para. 0016]. Therefore, teaching a method of treating cancer in a human subject as recited by clam 1.
The microorganisms for use in the methods and compositions, combinations and kits, including diagnostic and pharmaceutical compositions, contain a microorganism [abstract]. The microorganism employed in the methods can be one that can form a mutual or commensal association with the subject, such as strains of Bifidobacterium breve [para. 0021] and Bifidobacterium animalis [para 503]; teaching claims 1, 3, 36-37 and 41. Previous studies have postulated that anaerobic bacteria are preferred for administration to tumors. Cancers can also be cancer-forming solid tumors, malignant melanoma, non-melanoma skin cancers, as well as hematologic tumors and/or malignancies, acute and chronic leukemia. chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm and cancers associated with AIDS [para 590]; thereby teaching claims 39 and 40.
The dosage regimen can be any of a variety of methods and amounts, and can be determined by one skilled in the art according to known clinical factors [para 616]. Modes of administration for a co-administered substance can be the same mode of administration as the microorganism or cell or can be via a different mode of administration. Modes of administration can include, but are not limited to, intravenous, subcutaneous, intramuscular, intratumor, oral, subcutaneous, administration [para 624]. Thus teaching instant claims 6 and 19. Thus, dosages delivered directly into a tumor can be administered at lower effective dosages [para. 616]. Exemplary levels for administering a bacterium to a 65 kg human can include 1×106 or about 1×106 cfu, 1×107 or about 1×107 cfu, 5×107 or about 5×107 cfu [para. 616]; teaching claim 7. The methods provided herein can include multiple administrations of a microorganism to a subject [para. 618].
Therapeutic agents for the compositions, methods and uses provided herein can be, for example, an anti-cancer agent. Anti-cancer agents provided herein include, but are not limited to, anti-cancer antibiotics, anti-cancer antibodies [para. 0040]. Stritzker et al., teach a combination, comprising a bacterium; and an anti-tumor or anti-cancer agent [claim 131]. An anti-cancer agent or compound (used interchangeably with “anti-tumor or anti-neoplastic agent”) refers to any agents, or compounds, used in anti-cancer treatment. These include any agents, when used alone or in combination with other compounds, that can alleviate, reduce, ameliorate, prevent, or place or maintain in a state of remission of clinical symptoms or diagnostic markers associated with neoplastic disease, tumors and cancer, and can be used in methods, combinations [para. 0072].
Therefore Stritzker et al., teach a method of treating cancer in a human subject comprising co-administering to the subject an anti-cancer antibody and a bacterial formulation comprising genus Bifidobacterium, wherein the bacterial formulation comprises bacteria selected from the group consisting of Bifidobacterium animalis and Bifidobacterium breve wherein the anti-cancer antibody is an immune checkpoint inhibitor. However, Stritzker et al., do not teach anti-cancer antibodies also an immune checkpoint inhibitor such as anti-PD-1, anti- PD-L1 or anti-CTLA-4.
Korman et al., has been discussed above as teaching methods for treating cancer, using anti-PD-1 antibodies as known as ICI, just as instantly claimed.
Therefore, it would have been prima facie obvious at the time of applicants’ invention to incorporate Korman et al., anti-PD-1 antibodies (anti-cancer antibodies) which are immune checkpoint inhibitors already known to treat solid tumors and melanomas into Stritzker et al., method of treating cancer in a human subject comprising administering to the subject an anti-cancer antibody and a bacterial formulation when Stritzker et al., already it was known to treat cancer in a human subject comprising administering to the subject bacterial formulations in combination with other anti-cancer antibody therapies to treat cancer. One of ordinary skill in the art would have a reasonable expectation of success by combining both components because the prior art teach combination therapy was well known to produce beneficial cancer treating results by interfering with PD-1 and reducing PD-1 expression and using bacteria to treat the site of carcinoma proliferation.
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take a method of treating cancer when each ingredient is well-known to treat cancer, and where there is no change in the respective function of immune check point inhibitor or the bacteria thus the combination would have yielded a reasonable expectation or success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
8. Applicant's arguments filed April 13, 2026 have been fully considered but they are not persuasive.
The rejection of claims 1, 3, 6-7, 19, 30-31, 33-35, 39 and 40-42 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Stritzker et al., in view of Korman et al., is maintained for reasons of record.
Applicants argue that the prior art does not teach “…wherein the bacterial formulation enhances an anti-cancer immune response by the immune checkpoint inhibitor.” However contrary to Applicants assertion, Stritzker et al., teach a probiotic microorganism, such as B breve, can stimulate a host to produce antimicrobial molecules, alter a host's immune response, stimulate mucosal barrier function or alter immunoregulation, such as by decreasing pro-inflammatory molecules and promoting protective molecule. Additionally, the bacteria can attenuate pathogenicity, reduce toxicity, produce preferential accumulation in tumor, increase the ability to activate an immune response against tumor cells, increase immunogenicity, increase or decrease replication competence, and express exogenous proteins, and combinations thereof. The B breve is selected or designed for enhancing the capacity of a target cell or tissue to bind, transport, metabolize, store and/or accumulate. The anti-tumor immune response can result in, or enhance, inhibition of tumor growth, shrinkage, and/or elimination of the tumor. Therefore the bacterial formulation enhances an anti-cancer immune response by the immune checkpoint inhibitor. Applicants are reminded that none of the rejected claims specifically define what particular anti-cancer immune response is being enhanced.
Additionally, Korman et al., teach the antibodies of the invention exhibit functional properties, such as high affinity binding to PD-1, the ability to stimulate T cell proliferation, IFN-γ and/or IL-2 secretion in mixed lymphocyte reactions, the ability to inhibit binding of one or more PD-1 ligands (e.g., PD-L1 and/or PD-L2), and the ability to stimulate antibody responses and/or the ability to inhibit growth of tumor cells in vivo. Accordingly, this argument is not persuasive.
Claim Rejections - 35 USC § 103
9. Claims 1, 3, 6-7, 19, 30-31, 33-35, 39 and 40-42 are rejected under 35 U.S.C. 103 as being unpatentable over Langermann (US Patent Pub. 2013/0017199 published Jan. 2013) in view of Stritzker et al., (US Patent Pub 2008/0193373 published August 2008).
Langermann teach methods and compositions for treating cancer that results from (1) failure to elicit rapid T cell mediated responses, (2) induction of T cell exhaustion, T cell anergy or both, or (3) failure to activate monocytes, macrophages, dendritic cells and/or other APCs, for example, as required to kill intracellular pathogens. The method and compositions solve the problem of undesired T cell inhibition by simultaneously inhibiting the PD-1 ligands, PD-L1 and PD-L2 [abstract]. The immune response can be modulated by providing antagonists which bind with different affinity, by varying the dosage of agent which is administered, by intermittent dosing over a regime, and combinations thereof, that provides for dissociation of agent from the molecule to which it is bound prior to being administered again [abstract]. The immunomodulatory compositions and methods for treating diseases such as cancer or infections, in particular to diseases inducing T cell exhaustion, T cell anergy, or both, or diseases [para. 0001]. Langermann teach the treatment of one or more symptoms of cancer and/or induction of tumor immunity. Exemplary tumor cells that can be treated, include but not limited to, sarcoma, melanoma, lymphoma, leukemia, neuroblastoma, or carcinomas [para. 22] thereby teaching claims 39-40.
A preferred embodiment, the compositions simultaneously block both PD-L1 and PD-L2 mediated signal transduction in T cells, which have differential effects on T cell activity. Blocking PD-L1 mediated signal transduction induces robust effector cell responses, such as increasing the number of infiltrating IFNγ producing T cells and M1 macrophages. Blocking PD-L2 mediated signal transduction decreases the number of infiltrating Tregs. This decrease in Tregs can increase the number of Th17 cells and the level of IL-17 production, and also reduce the number of PD-1 positive cells. Therefore, simultaneous blocking of two independent PD-1 ligands can enhance two different beneficial T cell activities. Preferred compositions include immunomodulatory agents that bind directly to PD-1, PD-L1, PD-L2, or a combination thereof and increase or activate T cell responses, such as T cell proliferation or activation [para. 0016]; thereby teaching claim 41. Preferred immunomodulatory agents interfere with or inhibit the interaction between the endogenous ligands of PD-1 and PD-1. For example, the immunomodulatory agent interferes with, inhibits, or blocks PD-L1 and PD-L2 or both ligands from interacting with PD-1 [para 0061]. Additional embodiments include antibodies that bind to PD-L2, PD-L1, PD-1 or B7-1 polypeptides, and variants and/or fragments thereof [para 0065]; thereby teaching clam 31 and 33. The immunomodulatory agents are administered to initiate an immune response, stimulate an immune response, or enhance an immune response. In some aspects, the immunomodulating agent is AMP-224. AMP-224 can be administered as a bolus dose at a specific dosage. In another aspect, AMP-224 is administered [para. 0482] thereby teaching claims 30-31 and 34. Langermann et al., teach an antibody such as MDX-1106, the PD-L2-Ig fusion protein [[para. 481]; thereby teaching claim 30 and 34.
The compositions can be administered in combination or alternation with a vaccine containing one or more antigens such as bacterial antigens [para 0024]. Vaccines require strong T cell response to eliminate infected cells. Immunomodulatory agents described herein can be administered as a component of a vaccine to promote, augment, or enhance the primary immune response and effector cell activity and numbers. Vaccines include antigens, the immunomodulatory agent (or a source thereof) and optionally other adjuvants and targeting molecules. Sources of immunomodulatory agent include any of the disclosed PD-L1, PD-L2 or PD-1 polypeptides, fusion proteins, or variants thereof, nucleic acids encoding any of these polypeptides, or host cells containing vectors that express any of these polypeptides [para. 418]. The antigen can be derived from a bacterium, and can be a whole cell [para. 420]. The antigens are whole inactivated or attenuated organisms. These organisms may be bacteria [para. 421].
Pharmaceutical compositions containing peptides or polypeptides may be for administration by parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), transdermal (either passively or using iontophoresis or electroporation), or transmucosal (nasal, vaginal, rectal, or sublingual) routes of administration [para 403] thereby teaching claim 19. Antagonists of PD-1 can also be formulated for oral delivery [para 415]; thereby teaching claim 6.The dose of immunomodulatory agent enhances an immune response to an antigen in a human [para 468]. Therefore, Langermann teaches a method of treating cancer in a human subject comprising co-administering to the subject an immune checkpoint inhibitor wherein the immune checkpoint protein is anti-PD-1 or anti-PD-L1 and the checkpoint immune inhibitor and a whole cell bacterial formulation; but does not specifically recite the Bifidobacterium species.
Stritzker et al., has been discussed above as teaching a method of treating cancer in a human subject comprising administering to the subject an anti-cancer antibody and a bacterial formulation comprising bacteria of at least one of the species Bifidobacterium animalis, and Bifidobacterium breve.
Therefore, it would have been prima facie obvious at the time of applicants’ invention to incorporate Stritzker et al’s whole cell Bifidobacterium bacterial formulation to treat cancer within the method of treating cancer as taught by Langermann in order to treat cancer using combination therapy. One of ordinary skill in the art would have a reasonable expectation of success by combining the components because the prior art teach combination therapy was well known to produce beneficial by promoting, augmenting, or enhancing the primary immune response and effector cell activity and numbers while also decreasing PD-1 expression and blocking PD-1.
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take a method of treating cancer when each ingredient is well-known to treat cancer, and where there is no change in the respective function of immune check point inhibitor, or the bacterial formulation; thus the combination would have yielded a reasonable expectation or success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
10. Applicant's arguments filed April 13, 2026 have been fully considered but they are not persuasive.
The rejection of claims 1, 3, 6-7, 19, 30-31, 33-35, 39 and 40-42 under 35 U.S.C. 103 as being unpatentable over Langermann in view of Stritzker et al., is maintained for reasons of record.
Applicants argue that the prior art does not teach “…wherein the bacterial formulation enhances an anti-cancer immune response by the immune checkpoint inhibitor.” However contrary to Applicants assertion, Langermann teach sources of immunomodulatory agent include any of the disclosed PD-L1, PD-L2 or PD-1 The antigen can be derived from a whole cell bacterium. Immunomodulatory agents described herein can be administered as a component of a vaccine to promote, augment, or enhance the primary immune response and effector cell activity and numbers. The immunomodulatory agents are administered to initiate an immune response, stimulate an immune response, or enhance an immune response.
Stritzker et al., teach a probiotic microorganism, such as B breve, can stimulate a host to produce antimicrobial molecules, alter a host's immune response, stimulate mucosal barrier function or alter immunoregulation, such as by decreasing pro-inflammatory molecules and promoting protective molecule. Additionally, the bacteria can attenuate pathogenicity, reduce toxicity, produce preferential accumulation in tumor, increase the ability to activate an immune response against tumor cells, increase immunogenicity, increase or decrease replication competence, and express exogenous proteins, and combinations thereof. The B breve is selected or designed for enhancing the capacity of a target cell or tissue to bind, transport, metabolize, store and/or accumulate. The anti-tumor immune response can result in, or enhance, inhibition of tumor growth, shrinkage, and/or elimination of the tumor. Therefore the bacterial formulation enhances an anti-cancer immune response by the immune checkpoint inhibitor. Applicants are reminded that none of the rejected claims specifically define what particular anti-cancer immune response is being enhanced. Thus, the rejection is maintained.
Claim Rejections - 35 USC § 103
11. Claims 32 and 36-37 are rejected under 35 U.S.C. 103 as being unpatentable over Langermann (US Patent Pub. 2013/0017199 published Jan. 2013) and Stritzker et al., (US Patent Pub 2008/0193373 published August 2008) as applied to claims 1, 3, 6-7, 19, 30-31, 33-35, 39 and 40-42 above, and further in view of Feltquate et al., (WO 2015176033/CA 2949121 published Nov. 19, 2015 priority to May 2014). The rejection is stated in full within the Office Action dated March 5, 2025.
Langermann and Stritzker et al., teach a method of treating cancer in a human subject comprising co-administering to the subject an immune checkpoint inhibitor wherein the immune checkpoint inhibitor is an anti-PD-1/anti-PD-L1 and anti-CTLA-4 antibody and a bacterial formulation comprising Bifidobacterium animalis and/or Bifidobacterium breve. However, neither teach the anti-PD-1/anti-PD-L1 antibody is pembrolizumab or MSB-0010718C.
Feltquate et al., teach a method for treating a subject afflicted with a cancer, which method comprises administering to the subject therapeutically effective amounts of: (a) an anti-cancer agent which is an antibody or an antigen-binding portion thereof that specifically binds to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity; and (b) another anti-cancer agent [abstract]. In the past decade, intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of an antibody (Ab), ipilimumab, that binds to and inhibits CTLA-4 for the treatment of patients with advanced melanoma and the development of Abs such as nivolumab and pembrolizumab (formerly lambrolizumab) that bind specifically to the Programmed Death-1 (PD-1) receptor and block the inhibitory PD-1/PD-1 ligand pathway [para. 4]. The anti-PD-1 Ab is pembrolizumab. Pembrolizumab has been approved by the FDA for the treatment of relapsed or refractory melanoma [para. 68]. The anti-PD-1 Ab is nivolumab. Nivolumab (also known as "OPDIV00"; formerly designated 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor Ab that selectively prevents interaction with PD-1 ligands (PD-Li and PD-L2), thereby blocking the down-regulation of antitumor T-cell functions [para 68]. The anti-PD-1 Ab can be MEDI0608 (formerly AMP-514), which is a monoclonal antibody [para. 70]. The anti-PD-1 antibody is Pidilizumab (CT-011), which is a humanized monoclonal antibody [para. 70]. The anti-CTLA-4 Ab is ipilimumab [para 11]. In certain embodiments, the anti-PD-L1 Ab is BMS-(formerly 12A4 or MDX-1105). In other embodiments, the anti-PD-L1 Ab is MPDL3280A (also known as RG7446), MEDI4736 (also called Durvalumab; or MSB0010718C (also called Avelumab) [para 77]. Therefore, Feltquate et al., teach claims 30, 32, 34, and 36-38. For administration of an anti-PD-1 Ab, especially in combination with another anti-cancer agent, provides the optimum desired response, e.g., a maximal therapeutic response and/or minimal adverse effects [para. 93]. The therapeutic agents can be constituted for the carrier for a composition containing an Ab is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration, parenteral, e,g., oral, administration.
Thus, it would have been prima facie obvious at the time of applicants’ invention to incorporate, Feltquate et al’s anti-PD-1, anti-PD-L1 and/or anti CTL4-A antibodies into Langermann and Stritzker et al., method of treating cancer in a human subject comprising co-administering to the subject an immune checkpoint inhibitor antibody such as anti-PD-1/anti-PD-L1 and anti-CTLA-4 antibody and a bacterial formulation comprising Bifidobacterium animalis and/or Bifidobacterium breve
because Feltquate et al., taught pembrolizumab or MSB-0010718C is an the anti-PD-1 and/or anti-PD-L1 antibodies known to promote cancer disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of cancer disease symptom-free periods, or a prevention of impairment or disability due to the cancer disease affliction and result in a reduction in tumor growth or size of the tumor.
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take a method of treating cancer when each ingredient is well-known to treat cancer, and where there is no change in the respective function of immune check point inhibitors, or the bacterial formulation; thus the combination would have yielded a reasonable expectation or success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
12. Applicant's arguments filed April 13, 2026 have been fully considered but they are not persuasive. The rejection of claims 32 and 36-37 under 35 U.S.C. 103 as being unpatentable over Langermann and Stritzker et al., as applied to claims 1, 3, 6-7, 19, 30-31, 33-35, 39 and 40-42 above, and further in view of Feltquate et al., is maintained for reasons of record.
Applicants argue that the prior art does not teach “…wherein the bacterial formulation enhances an anti-cancer immune response by the immune checkpoint inhibitor.” Langermann has been discussed above as teaching sources of immunomodulatory agent include any of the disclosed PD-L1, PD-L2 or PD-1. The antigen can be derived from a whole cell bacterium. Immunomodulatory agents described herein can be administered as a component of a vaccine to promote, augment, or enhance the primary immune response and effector cell activity and numbers. Feltquate et al’s anti-PD-1, anti-PD-L1 and/or anti CTL4-A antibodies into Langermann and Stritzker et al., method of treating cancer in a human subject comprising co-administering to the subject an immune checkpoint inhibitor antibody such as anti-PD-1/anti-PD-L1 and anti-CTLA-4 antibody and a bacterial formulation comprising Bifidobacterium animalis and/or Bifidobacterium breve because Feltquate et al., taught pembrolizumab or MSB-0010718C is an the anti-PD-1 and/or anti-PD-L1 antibodies known to promote cancer disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of cancer disease symptom-free periods, or a prevention of impairment or disability due to the cancer disease affliction and result in a reduction in tumor growth or size of the tumor. Thus, the rejection is maintained.
Pertinent Art
13. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Zitvogel et al., (WO2015075688 published 2015-05-28, priority to 2013-11-21) teach the intestinal microbiota modulates the anti-cancer immune effects of cancer treatment with anti-CTLA-4 antibodies where Bifidobacterium is beneficial and favorable when abundantly present. Bifidobacterium is associated with the upregulation of T-bet evidencing that a pTh17 T cell response had been elicited upon co-administration with ICIs such as anti-CTLA-4 antibodies.
O’Mahoney et al., teach that Bifidobacterium strains or formulations are used in the preparation of anti-inflammatory biotherapeutic agents for reducing the levels of pro inflammatory cytokines. No more than routine skill is required to co-administer an ICI, which is known to cause the immune related adverse inflammation with Bifidobacterium, an anti-inflammatory biotherapeutic which also treats tumor, tumor tissue, cancers and/or metastasis.
Sivan et al., (Published 5 November 2015 on Science Express) teach commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy.
Iida et al., (Science. 2013 Nov 22;342(6161):967-70) teach the gut microbiota influences both local and systemic inflammation. Inflammation contributes to development, progression, and treatment of cancer. Thus, optimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.
As the evidence of record demonstrates, immune checkpoint inhibitors and the claimed species of Bifidobacteria are cancer therapeutics that could be co-administered and expected to work side-by-side.
Conclusion
14. No claims allowed.
15. 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.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Peter Paras, can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
/JANA A HINES/Primary Examiner, Art Unit 1645
Prosecution Insights