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 .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on August 5, 2025 has been entered.
Claim Amendment
3. The amendment of August 5, 2025 has been entered. Claim 1 has been amended. Claims 2, 4-5, 8-18, 20-29 and 38 have been cancelled. Claims are under consideration in this Office Action.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on October 2, 2025 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
5. Claim 34 is objected to because of the following informalities: Claim 34 is drawn to anti-PD-1 antibodies, however MPDL3280A is traditionally known as an anti-PD-L1 antibody. Appropriate correction is required.
Maintained Grounds of Rejection
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.
6. Claims 1, 3, 19, 30-31, 33-35, 39 and 40-41 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.
The rejection is stated in full within the Office Action dated March 5, 2025.
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.
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).
The rejection is stated in full within the Office Action dated March 5, 2025.
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.
Claim Rejections - 35 USC § 103
8. Claims 1, 3, 6-7, 19, 30-31, 33-35, 39 and 40-41 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). The rejection is stated in full within the Office Action dated March 5, 2025.
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.
Claim Rejections - 35 USC § 103
9. 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 40-41 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.
Therefore, 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
10. Applicant's arguments filed August 5, 2025 have been fully considered but they are not persuasive.
The rejection of claims 1, 3, 19, 30-31, 33-35, 39 and 40-41 under 35 U.S.C. 103 as being unpatentable over Linnebacher and in view of Korman et al., is maintained for reasons of record.
The rejection of claims 1, 3, 6-7, 19, 30-31, 33-35, 39 and 40-41 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.
The rejection of claims 1, 3, 6-7, 19, 30-31, 33-35, 39 and 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Langermann in view of Stritzker et al.,
is maintained for reasons of record.
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 40-41 above, and further in view of Feltquate et al., is maintained for reasons of record.
Applicants argue 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.
Contrary to Applicants assertion, Bifidobacterium animalis and Bifidobacterium breve do not have an inhibitory effect on the T-cell immune response of ICIs. Bifidobacterium animalis and Bifidobacterium breve do not inhibit the T-cells response to ICIs. The state of the art in 2014 was that Bifidobacterium breve is as effective as budesonide at reducing inflammation in a murine model. Bifidobacterium breve induced regulatory T cell responses by augmenting the intensity of Foxp3 in blood CD4+ T cells (See Sagar et al., Respir Res. 2014 Apr 16;15(1):46). Furthermore, O’ Mahoney et al. (US 2012/0276143); Okada et al. (Int J Exp Pathol. 2009 Apr; 90(2): 131-140); Ouwehand et al. (FEMS Immunol Med Microbiol. 2008 Jun;53(1):18-25); and Salazar et al. (Biomed Res Int. 2014; 2014: 106290), do not teach that Bifidobacterium inhibits the T-cells response elicited by ICIs. O’Mahoney et al., teach that Bifidobacterium strains are used in the preparation of anti-inflammatory biotherapeutic agents for reducing the levels of pro inflammatory cytokines. Salazar et al., teach EPS-producing B. animalis in healthy rats is associated with an immune protective profile, since this EPS producing strain can suppress the proinflammatory cytokine IL-6 and promote the synthesis of the regulatory cytokine TGF-β.
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. Therefore the argument that Bifidobacterium inhibits the T-cell immune response of ICIs is not persuasive.
In further response to Applicants arguments, Immune checkpoint inhibitors (ICIs) activate the immune system by blocking the "brakes" that T-cells use to prevent attacking healthy cells. This can lead to an overactive immune response, causing inflammation as an adverse effect, known as an immune-related adverse event (irAE). Treatment for these inflammatory side effects often involves anti-inflammatory drugs. In this case, Applicants state that Bifidobacterium animalis and Bifidobacterium breve have an anti-inflammatory. As evidenced by Applicant, 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. Moreover, Korman et al., teach pharmaceutical compositions administered as combination therapy, i.e., combined with other agents. For example, the combination therapy can include an anti-PD-1 antibody combined with at least one other anti-inflammatory or immunosuppressant agent. Therefore it was well known in the art before the time of the instant 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 cancers and tumors.
Thus, Applicants anti-inflammation argument bolsters the Office’s position regarding the co-administration of ICIs and Bifidobacterium. Striker et al., teach a probiotic microorganism also 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 molecules [para 56]. Inflammation involves the movement of fluid and cells (e.g., white blood cells or leukocytes, neutrophils, monocytes and T- and B-cells) into the affected area, site or tissue. The immune system can trigger an inflammatory response in the absence of a typical insult. Such excessive, misdirected and/or inappropriate immune inflammatory responses can lead to damage of normal, healthy body tissues and are associated with certain diseases and disorders, including, for example, autoimmune diseases and disorders. There are a number of diseases and disorders that can involve inflammation, both neoplastic and non-neoplastic or non-malignant (benign) diseases [para 70]. Therefore Striker et al., clearly teach the need for the anti-inflammatory Bifidobacterium to reduce inflammation caused by the administration of ICIs to simultaneously treat cancer and reduce inflammation.
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. This bolsters the Office
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. One of ordinary skill at the time would know that optimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. Furthermore, there were no known immunosuppressive effects upon T-cells by Bifidobacterium animalis and Bifidobacterium breve that would counteract the T-cell effect of the immune checkpoint inhibitor.
Therefore, Applicants arguments are not persuasive and the rejections will be maintained.
Conclusion
11. No claims allowed.
12. . 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 Gary Nickol, can be reached on 571-272-0835. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANA A HINES/Primary Examiner, Art Unit 1645