Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08 August 2025 has been entered.
PRIORITY
The Applicant claims priority to EP14190167.8, filed on 23 October 2014. The foreign document does not provide support for Bacteroides cepacia (recited in claim 45). It does not provide support for Bacteroides salyersiae, Bacteroides acidifaciens, Bacteroides intestinalis, Bacteroides vulgatus or Burkholderia cenocepacia (as recited in claim 46).
The Applicant claims priority to EP15162097.8, filed on 31 March 2015. The foreign document does not provide support for Bacteroides salyersiae, Bacteroides acidifaciens or Bacteroides intestinalis (as recited in claim 46).
CLAIMS UNDER EXAMINATION
Claims 45-46, 48, 50, 52 and 61-66 have been examined on their merits.
WITHDRAWN REJECTIONS
The rejection of claims 45-46,48, 50, 52 and 61-66 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, has been withdrawn due to claim amendment.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 45-46, 48, 50, 52, 62-63 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Mazmanian et al. (previously cited; Probiotic Prevention And Treatment Of Colon Cancer. US 2014/0335131 13 November 2014 with benefit of Provisional application 61/822126, filed on 10 May 2013) in view of Perez-Chanona et al. (From promotion to management: The wide impact of bacteria on cancer and its treatment. Bioessays: 658664 2014) and Korman et al. (previously cited; Human CTLA-4 Antibodies And Their Uses. Patent 8017114 2011).
Mazmanian et al. teach a method for treating colorectal cancer ([0005]). Subject at various stages of tumor development and metastasis can be treated ([0093]). The art teaches
adjusting the composition of gut microbiota in the subject by administering a composition comprising Bacteroides bacteria ([0010]). The Bacteroides can be B. fragilis or B. thetaiotaomicron ([0011]).
Mazmanian teaches the following at [0067]:
the bacteria may be administered at a dose of at least 103 CFU, optionally at least 104 CFU, optionally at least 105 CFU, optionally at least 106 CFU, optionally at least 107 CFU, optionally at least 108 CFU, or optionally at least 109 CFU. In some embodiments, the bacteria may be administered at a dose of 103 to 1012 CFU, optionally at a dose of 104 to 1011 CFU, optionally at a dose of 105 to 1010 CFU, optionally at a dose of 106 to 1010 CFU, or optionally at a dose of 107 to 1010 CFU. In some embodiments, the bacteria may be administered at optionally at a dose of 107 to 1010 CFU. In some embodiments, the bacteria may be administered at optionally at a dose of 5×109 to 7×1010 CFU.
Mazmanian teaches the composition comprising bacteria can be administered alone or in combination with one or more additional probiotic, nutraceutical or therapeutic agents ([0063]).
The following is also noted:
Mazmanian teaches testing for “dysbiosis in the subject” ([0015]). Mazmanian teaches
“another risk factor that may increase a subject's susceptibility to colorectal tumorigenesis is the composition of gut microbiota. Shifts in the intestinal microenvironment may lead to changes in the microbiota known as dysbiosis, which in turn may increase susceptibility to intestinal inflammation and colorectal tumorigenesis” ([0054]). The art identifies decreased colonization of Bacteroides bacteria as a dysbiosis condition that may contribute to colorectal cancer tumorigenesis ([0054]). As evidenced by the Instant Specification, Bacteroides are gram negative bacteria ([0088]). Therefore the art teaches dysbiosis can be caused by decreased colonization of Bacteroides (gram negative) bacteria.
The art teaches identifying the subject in need of treatment based on the presence of dysbiosis ([0097]). The art teaches administering bacteria, including Bacteroides, to “fully restore” normal colonization ([0064]). The art teaches the gut microbiota is adjusted ([0060] [0064]). The gut is interpreted to read on the digestive tract. An amount that fully restores normal colonization is broadly interpreted to read on an amount “sufficient to colonize the digestive tract of the patient”.
Mazmanian treats a patient with cancer. The patient can have dysbiosis. The dysbiosis can be caused by decreased colonization of Bacteroides. Mazmanian teaches a therapeutic agent can be administered in combination with Bacteroides bacteria to treat cancer.
The deficiencies of the art are:
the art does not teach the dysbiosis is caused by an antibiotic that kills gram negative bacteria; and
the art does not teach administering an anti-CTLA4 monoclonal antibody.
Perez-Chanona teach chemotherapeutic drugs put patients in danger of developing bacteremia or GI-associated sepsis (see page 661, left column, third paragraph). Consequently, the standard of care is to treat patients with antibiotics, especially those targeting gram-negative bacteria (same cited section). Perez-Chanona et al. teach dysbiotic microbiota is thought to contribute to the initiation and progression of colorectal cancer (CRC) (Abstract).
Perez-Chanona teach microbial community disruption by means of antibiotic
treatments impaired efficacy of chemotherapeutic drug treatment on distant tumors, implying a beneficial effect of microbes on cancer management (page 661, left column, third paragraph).
Korman teaches a method for treating cancer in a subject, the method comprising administering an anti-CTLA-4 antibody (see claim 1 of Korman). The cancer can be colon cancer (column 39, lines 45-50). The antibody can be administered in combination with anti-cancer therapy (column 9, lines 33-36). Korman teaches the dose administered can be between 1-10 mg/kg (column 34, line 66). Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response) (column 33, lines 52-53).
It would have been obvious to treat a patient with a dysbiosis caused by an antibiotic. Mazmanian treats a cancer patient with dysbiosis and Perez-Chanona teaches dysbiosis can be caused by antibiotics that kill Gram negative bacteria. One would have been motivated to administer the Gram negative bacteria taught by Mazmanian to restore the bacteria causing the dysbiosis. One would have had a reasonable expectation of success since Mazmanian teaches the disclosed method can be used in patients with dysbiosis caused by Bacteroides. One would have expected similar results since both references are directed to dysbiosis in patients with colon cancer.
It would have been obvious to combine the teachings of the prior art by administering the probiotics taught by Mazmanian and an anti-CTLA-4 antibody. Mazmanian teaches administering a therapeutic agent in combination with Bacteroides bacteria to treat colon cancer and Korman teaches anti-CTLA-4 antibody is a therapeutic for colon cancer. The skilled artisan would combine two therapies that are known to treat colon cancer for an improved effect. The MPEP teaches it is prima facia obvious to combine two compositions, each of which is taught by the prior art to be used for that very same purpose. Perez-Chanona teaches microbiota have a beneficial effect on cancer therapy. Therefore combining the therapies taught by Mazmanian and Korman would be expected to increase the anticancer effects of the therapeutic taught by Korman as claimed. One would have had a reasonable expectation of success since Mazmanian teaches cancer therapeutics can be administered with the disclosed bacteria. One would have expected similar results since Mazmanian and Korman treat the same disorder.
It would have been obvious to administer 3-10 mg/kg anti-CTLA4 antibody. Korman teaches the dose administered can be between 1-10 mg/kg. One would optimize the dose since Korman teaches dosage regimens are adjusted to provide the optimum desired response MPEP 2133.03.
The rejections under 35 USC 103 above are consistent with case law. Applicants are referred to In re Kerkoven (205 USPQ 1069) in which it was shown to be prima facia obvious to combine two compositions, each of which is taught by the prior art to be used for that very same purpose. Ex Parte Quadranti (25 USPQ2d 1071) also sets forth this precedent, in that the use of materials in combination, each of which is known to function for the intended purpose, is generally held to be prima facia obvious. Ex parte Kucera (165 USPQ 332) clearly states that synergism has no magical status in rendering otherwise obvious subject matter patentable.
Therefore claim 45 is rendered obvious.
Manzamanian teaches the composition may comprise a mixture of B. fragilis, B. thetaiotaomicron, B. vulgatus ([0011]).Therefore claim 46 is included in this rejection.
Mazmanian discloses the bacteria can be administered orally ([0011]). Therefore claim 48 is included in this rejection.
Mazmanian teaches the following ([0093]):
Subjects at various stages of colorectal cancer may be treated with the presently disclosed methods. For example, a subject may be treated with the presently disclosed methods
at the precancer or tumor budding stage, at the dysplasia stage, before or after the tumor invades submucosa, before or after the tumor invades muscularis propria, before or after the
tumor invades subserosa or beyond, before or after the tumor invades adjacent organs, before or after the tumor perforates the visceral peritoneum, before or after metastasis, before or
after surgery, radiation therapy or chemotherapy, before or after remission, etc.
Therefore Mazmanian discloses treatment with the bacterial composition at any time, and teaches administration before or after therapy. It is of note the art teaches the disclosed probiotic composition can be administered with a therapeutic agent “in any order” ([0063]). Therefore claim 50 is rendered obvious.
Mazmanian teaches the disclosed probiotic composition can be used before or after radiation therapy (hence, radiotherapy) [0093]. Therefore claim 52 is rendered obvious.
Mazmanian teaches, the composition may comprise B. fragilis and B. thetaiotaomicron ([0062]). Therefore claims 62-63 are included in this rejection.
Mazmanian teaches the composition can be administered via fecal transplantation ([0011]). Therefore claim 66 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claim 61 is rejected under 35 U.S.C. 103 as being unpatentable over Mazmanian in view of Perez-Chanona and Korman as applied to claim 45 above, and further in view of Iida et al. (Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment. Science. 2013 November 22; 342(6161): 967–970 as evidenced by National Library of Medicine (Neomycin. Updated 2019 Apr 12).
Claim 45 is rejected on the grounds set forth above. The teachings of Mazmanian, Perez-Chanona and Korman are reiterated. Perez-Chanona teaches an antibiotic that targets Gram-negative bacteria cause dysbiosis. The art is silent regarding a broad spectrum antibiotic.
Iida (disclosed as reference 38 in Perez-Chanona) teaches the gut microbiota influences both local and systemic inflammation. Inflammation contributes to development, progression, and treatment of cancer (Abstract). The art teaches disruption of the microbiota impairs the response of subcutaneous tumors to immunotherapy and platinum chemotherapy. The art teaches mice (subjects) treated with antibiotics respond poorly to therapy. See Abstract. Iida discloses treatment with an antibiotic cocktail comprising vancomycin, imipenem and neomycin (see page 2, second paragraph). As evidenced by National Library of Medicine, neomycin is a broad spectrum antibiotic (first sentence of page 1). The art teaches subjects with colon carcinoma (see page 2, second paragraph).
It would have been obvious to use the method taught by Mazmanian to treat dysbiosis caused by a broad spectrum antibiotic. One would have been motivated to do so since Mazmanian teaches a dysbiosis in subjects with colon cancer and Iida teaches treatment with broad spectrum antibiotics causes disruption in patients with the same disorder. One would have had a reasonable expectation of success since Mazmanian teaches the disclosed method can be used to treat patients with dysbiosis. One would have expected similar results since both references are directed to dysbiosis in patients with colon cancer. Therefore claim 61 is rendered obvious.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claims 64-65 are rejected under 35 U.S.C. 103 as being unpatentable over Mazmanian in view of Perez-Chanona and Korman as applied to claim 45 above, and further in view of Goodman et al. (previously cited; Prebiotic Formulations US2021/0100854 with benefit of Provisional Application 61/949058 filed on 06 March 2014).
Claim 45 is rejected on the grounds set forth above. The teachings of the prior art are reiterated. Mazmanian teaches the composition comprising Bacteroides bacteria, can be administered alone or in combination with one or more additional probiotic, nutraceutical, or therapeutic agents ([0063]).
The art is silent regarding administration of Burkholderia cepacia as an additional probiotic.
Goodman teaches a composition comprising a probiotic bacterium to treat a disease (Abstract). The composition can be used to correct or support dysbiotic gut flora ([0105] [0167]). The probiotic bacterium is selected to provide one or more of supporting anti-bacterial immunity, enhancing or supporting a healthy state in the subject, t enhancing or supporting the gastrointestinal barrier, or antagonizing disease-related bacterial infections. In another aspect, the probiotic bacterium is selected to prevent pathogen colonization and/or limit and/or clear the pathogen, and /or limit excessive inflammatory responses by down-regulating cytokine and chemokine production ([0091]). The art identifies Pseudomonas cepacia as a probiotic bacterium that can be used ([0092]). It is well known in the art that P. cepacia is also known as Burkholderia cepacia.
It would have been obvious to try using B. cepacia in the method taught by Mazmanian. One would have been motivated to do so since Mazmanian teaches a probiotic composition comprising bacteria that correct dysbiosis and Goodman identifies P. cepacian (B. cepacia) as a probiotic for correcting dysbiosis. The skilled artisan would use a probiotic known to correct dysbiosis in a composition used to treat dysbiosis. One would have had a reasonable expectation of success since Goodman teaches the species can be used in compositions to treat dysbiosis in the gut (hence, colon). One would have expected similar results since both references are directed to compositions for treating gut dysbiosis. Therefore claim 64 is rendered obvious.
It would have been obvious to try using Burkholderia cepacia and Bacteroides fragilis in the method taught by Mazmanian. One would have been motivated to do so since Mazmanian teaches a probiotic composition comprising B. fragilis that corrects dysbiosis and Goodman identifies P. cepacia (B. cepacia) as a bacteria that can be used as a probiotic for correcting dysbiosis. Applicants are referred to In re Kerkoven (205 USPQ 1069) in which it was shown to be prima facia obvious to combine two compositions, each of which is taught by the prior art to be used for that very same purpose. Ex Parte Quadranti (25 USPQ2d 1071) also sets forth this precedent, in that the use of materials in combination, each of which is known to function for the intended purpose, is generally held to be prima facia obvious. Therefore, then, barring unexpected results, one would reasonably expect enhanced, additive, or synergistic activity to be observed by combining the compositions or materials. One would have had a reasonable expectation of success since Goodman teaches B cepacia can be used in compositions to treat dysbiosis in the gut. One would have expected similar results since both references are directed to compositions for treat gut dysbiosis. Therefore claim 65 is rendered obvious.
Therefore Applicant’s Invention is rendered obvious as claimed.
37 CFR 1.132 Declaration
The Examiner acknowledges receipt of the Declaration under 37 CFR 1.132 by . Laurence Zitvogel filed on 08 August 2025. The Declaration under 37 CFR 1.132 is insufficient to overcome the rejection of claim 45:
The Declaration alleges “Mazamanian et al. never used colonization with B. fragilis to treat a cancer that had already developed”. The Declarant argues a person of ordinary skill in the art would not have been able to predict whether colonization with B. fragilis could be used to treat a cancer that had already developed.
In response: Mazamanian teaches administering Bacteroides to “reduce the progression” of colorectal cancer (Abstract; [0010]). At [0011] the art teaches the Bacteroides is one or more of B. fragilis, B. thetaiotaomicron, B. vulgatus, or a mixture thereof. Therefore the argument stating Manzamanian does not treat a patient with cancer is not persuasive.
The Declaration states Figure 4B illustrates administering B. fragilis restores the response to treatment with an anti-CTLA monoclonal antibody. The Declaration states “in germ free mice anti-CTLA4 antibodies have no antitumor effect”. The Declaration states B fragilis alone has no antitumor effect at all in these mice (bullet point 25 and 26 on page 5). The Declaration states Figure 4C demonstrates the claimed probiotic strains restore response to antibody treatment.
In response: As set forth above, Manzamanina teaches a subject with cancer can be treated with the disclosed Bacteroides. Korman teaches cancer can be treated with the disclosed antibody. The effect observed Figure 4B is obtained in a “germ free” mouse. As evidenced by Jackson Laboratory “germ free” mice are “free of all microorganisms, including those that are typically found in the gut”. A subject free of all gut microorganisms is not commensurate with the scope of claim 45. Claim 45 does not require complete absence of all microorganisms.
Regarding Figure 4C: The specification discloses oral administration of the claimed strains in mice treated with a combination of three broad-spectrum antibiotics (ampicillin, colistin, streptomycin, ACS) (see [0145]). The specification discloses broad spectrum antibiotics “deplete gut microbiota” ([0025]). Broad spectrum antibiotics kill positive and negative. Therefore Figure 4C discloses the effect observed when in mice with depleted gram positive and negative bacteria. This is not commensurate with the scope of claim 45.
The Declaration presents arguments directed to the Perez-Chanona reference. The Declaration states “the Examiner has generalized the alleged teachings of Perez-Chanona regarding the role of microbiota in the response to a treatment with a particular antibody (anti-ILR10 AB) to the treatment with any antibody whatsoever”.
In response: The rejection does not recite the use of an anti-ILR10 antibody, as alleged in the Declaration. Perez-Chanona is relied upon because it teaches the standard of care for treating cancer patients comprises administering antibiotics that kill gram-negative bacteria. Perez-Chanona is relied upon because it teaches antibiotic exposure can attenuate the microbial ecosystem and cause dysbiosis.
The Declaration argues Korman does not teach administering bacteria. The Declaration argues Manzamanian nor Korman provide any expectation of success that administering the claimed strains would increase the anticancer effects of the claimed antibody.
In response: Korman is not relied upon to teach administering a probiotic. Manzamanian administers the claimed Bacteroides to treat colon cancer. Manzamanian teaches administering an additional cancer therapy. Korman is relied upon because it teaches the claimed antibody can be used to treat colon cancer. One of ordinary skill would combine two therapies that are known to treat the same disorder.
Examiner notes the Declaration filed on 24 December 2024 (previously considered) states “the skilled artisan would understand the precise amount of bacteria administered is not critical” (see section 34). The Declaration states a synergistic effect occurs when a dose of anti-CTLA-4 mAB at “approximately 3.3 to 6.7 mg/kg” is administered (see page 5 section 31). Claim 45 encompasses of 3 mg/kg to 10 mg/kg. The claimed dose is not commensurate with the dose the cited as being critical.
Mazamanian teaches the bacteria may be administered at optionally at a dose of 107 to 1010 CFU . Korman teaches an anti-CTLA-4 antibody can be used to treat colon cancer. Korman teaches an anti-CTLA-4 antibody dose between 1-10 mg/kg. Because the Declaration states the amount of bacteria administered is not critical, one would expect to observe the synergistic effect recited in the Declaration when administering the dose of anti-CTLA-4 antibody taught by Korman.
Affidavits or declarations are provided as evidence and must set forth facts, not merely conclusions. In re Pike and Morris, 84 USPQ 235 (CCPA 1949).
Upon consideration of the facts taught by the prior art and the information submitted by the Affiant, the balance of evidence indicates that the prior art teaches the instantly claimed inventions.
APPLICANT’S ARGUMENTS
The arguments made in the response filed on 08 August 2025 are acknowledged. The Applicant argues the Examiner has not shown a reasonable expectation of success. The arguments state the Examiner does not contend that Applicant has not shown an unexpected, synergistic effect of the claimed combination. The arguments reiterate the remarks provided in the Declaration filed on 08 August 2025.
The Applicant argues Manzamanian does not treat a patient that already has cancer.
The arguments state Viaud et al. (not cited by Examiner) presented results suggesting that the gut microbiota help shape the anticancer immune response. The study disclosed Enterococcus hirae was identified as the bacterial species that increased the therapeutic effects of cyclophosphamide-based chemotherapy. Other bacteria did not show these effects. The Applicant states the instant application found Enterococcus hirae had no effect, while the claimed bacteria did. The skilled artisan could not have predicted these results prior to performing these experiments.
The Applicant reiterates the remarks in the Declaration directed to Figures 4B and 4C.
The arguments state it was demonstrated that a treatment with an anti-CTLA4 antibody is efficient only if the treated individual has a certain microbiota profile, and the inventors provided treatments which will improve the patient's responsiveness to a treatment by such an antibody.
The Applicant argues the Examiner has generalized the teachings of Perez-Chanona regarding the role of microbiota in the response to a treatment with a particular antibody (anti-ILR10 Ab) to the treatment with any antibody. The Applicant argues based on Perez-Chanona et al., a person of ordinary skill in the art would have understood that more investigations were required to identify microorganisms with the best immunological potential, a characteristic essential for enhancing chemotherapeutic drug efficacy.
The arguments state Korman et al. do not teach or suggest a method of treating cancer with any bacterial whatsoever.
EXAMINER’S RESPONSE
The arguments are not persuasive. Mazamanian teaches administering Bacteroides to “reduce the progression” of colorectal cancer (Abstract; [0010]). At [0011] the art teaches the Bacteroides is one or more of B. fragilis, B. thetaiotaomicron, B. vulgatus, or a mixture thereof. Therefore the argument that the art does not teach treating a patient with cancer us not persuasive.
The arguments directed to Perez-Chanona are acknowledged. The rejection does not rely on Perez-Chanona to teach the use of an anti-ILR10 antibody. Perez-Chanona is relied upon because it teaches the standard of care for treating cancer patients with antibiotics targeting gram-negative bacteria. The arguments directed to Viaud are acknowledged. Viaud is not cited as prior art. The rejection does not rely on a teaching of Enterococcus hirae.
The arguments directed to Korman are acknowledged. Korman is not relied upon to teach administering a probiotic. Korman is relied upon because it teaches the claimed antibody can be used to treat colorectal cancer.
The arguments directed to a synergistic effect are acknowledged. The Declaration filed on 24 December 2024 (previously considered) states “the skilled artisan would understand the precise amount of bacteria administered is not critical” (see section 34). The 2024 Declaration states a synergistic effect occurs when a dose of anti-CTLA-4 mAB at “approximately 3.3 to 6.7 mg/kg” is administered (see page 5 section 31). Claim 45 encompasses of 3 mg/kg to 10 mg/kg. The claimed dose is not commensurate with the dose the cited as being critical.
Mazamanian teaches the bacteria may be administered at optionally at a dose of 107 to 1010 CFU . Korman teaches an anti-CTLA-4 antibody can be used to treat colon cancer. Korman teaches an anti-CTLA-4 antibody dose between 1-10 mg/kg. Because the Declaration states the amount of bacteria administered is not critical, one would expect to observe the effect recited in the Declaration when administering the dose of anti-CTLA-4 antibody taught by Korman.
ART OF RECORD: (The Jackson Laboratory. The difference between germ free and specific-pathogen-free mice, first paragraph).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653