DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group III, claim 9, in the reply filed on 6/29/26 is acknowledged.
Claims 9 and new claims 11-14 are currently pending and under examination.
Claim Rejections - 35 USC § 112-2nd paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9 and 11-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 recites that the toxin is from a mutated E. coli which makes the claim confusing as it fails to teach the heterologous sequence/vector. It is not clear if the wording "A subunit of the heat-labile LT toxin from mutated Escherichia coli" refers to (1) a mutated A subunit of E. coli heat-labile LT toxin, or to (2) an A subunit of heat-labile LT toxin from a mutated E. coli (ie. from an E. coli carrying any mutation). Claim 1 is thus unclear. The Mycobacterium strain in the claimed method is a recombinant bacterium with a heterologous nucleic acid encoding a mutant E.coli A subunit of the heat labile toxin, wherein the A subunit is mutated at position 63 by a substitution from serine to lysine and the present wording does not convey this. Appropriate clarification or/correction is required.
Claim Rejections - 35 USC § 112-Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 9 and 11-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method for treating bladder cancer comprising administering to a subject in need thereof an effective amount of an immunological composition comprising a recombinant mutant Mycobacterium BCG strain, wherein the strain comprises a heterologous A subunit of a mutated E.coli heat-labile toxin wherein the A subunit is mutated at position 63 by a substitution of serine to lysine,
does not reasonably provide enablement for:
a method for treating an/or preventing any cancer using any recombinant Mycobacterium strain encoding the A subunit of the mutated heat-labile LT toxin (serine to lysine at position 63) from E. coli (let alone treating bladder cancer)
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/and or use the invention commensurate in scope with these claims.
Applicants stress in their response to the Restriction Requirement that the claimed method of treating bladder cancer uses the specific mutant strain (rBCG-LTAK63). See pages 6-19 of the Response to the Election dated 6/29/26. Pages 2-4 of the instant specification recite the safety history of use of the rBCG strains and their successful use as tuberculosis vaccines. Paragaraph [0011] recites BCG is the most widely used vaccine in the world with very low frequence of serious adverse side effects which makes it an excellent candidate as a vehicle for the presentation of heterologous antigens generating recombinant BCG-based vaccines and cites US Patent No. 6,673,353.
Paragraph [0006] recites:
In 1976, Morales, Eidinger and Bruce were the first to report the successful treatment of superficial bladder cancer with bacillus Calmette-Guérin (BCG) (Morales A, Eidinger D, Bruce AW. The Journal of Urology 1976; 116: 180 - 183). Since then, this immunotherapy in the form of intravesical BCG infusion has been used to treat and prevent recurrence of superficial bladder tumors. BCG has also shown efficacy against other types of tumors, such as melanoma, lung cancer, and leukemia (Patent US 5,712,123). [0007] Although the mechanism of the antitumor effect of BCG is not completely defined, there is a general consensus that intravesical application of BCG causes a nonspecific inflammatory reaction of the immune system. Thus, it leads to T cell activation and infiltration, inducing predominantly the production of cytokines related to the Th1 response, the major responsible for the antitumor effect. There is also stimulation of the Th2 response, such as the release of IL-4, IL-5, IL6 and IL-10 cytokines, which may be related to the local and systemic side effects of intravesical immunotherapy with BCG (Luo Y. et al. Clinical and experimental immunology 2006; 146: 181 - 188).
[0012] The immunotherapeutic mechanism of BCG was better understood with the identification of the genes responsible for the antitumor effect, enabling the production of recombinant organisms capable of stimulating a more intense Th1 response, aiming at a reduction of the dose to be employed and, consequently, fewer side effects. [0013] In this sense, the expression of immunogenic domains of bacteria, viruses and parasites has been successfully used in BCG, generating recombinant strains (rBCG) potentially useful in cancer immunotherapy. For example, the feasibility of using rBCG as a strategy for the expression of cytokines, pharmacological agents, and antitumor agents is already known in the state of the art, providing the basis for a new strategy to treat certain types of cancer (Patent US 5,776,465). The use of this strategy gives rBCG the ability to express specific proteins or polypeptides that act as cell growth inhibitors or as cytotoxic substances for cancer cells (e.g., interferon α or B, interleukins 1-7 or tumor necrosis factor α or ß). [0014] Furthermore, it has been shown that rBCG vaccines are able to promote both humoral and cellular immune response, being an option in the treatment of certain types of cancer. The possibility of using rBCG to express specific antitumor agents (Patent US 5, 776, 465) is also already known as a possible alternative in cancer treatment.
The specification demonstrates, that rBCG-LTAK63 produced markedly superior results and describes the LTAK63 construct as having the "unexpected technical effect of provoking a more intense antitumor immune response when compared to conventional BCG" and as generating compositions that are "more potent and effective than those comprising conventional BCG, or other rBCG. " In the MB-49 orthotopic bladder tumor model, rBCG-LTAK63 achieved.
However, the instant specification does not demonstrate results with any other strain as host cell, e.g., it only shows use of the BCG strain. The prior art shows the unpredictability of different strains of Mycobacterium in the vaccine art. BCG has a long safety history and was first administered to humans in 1921. Other strains of Mycobacterium have different immunogenic properties and safety profiles. There are no working examples in the instant specification to guide the skilled artisan in practicing the claimed method with any other strains of Mycobacterium. Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: “Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.”
Claim Rejections - 35 USC § 103
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.
Claim(s) 9 and 11-14 are is/are rejected under 35 U.S.C. 103 as being unpatentable over Hone, D (WO 2008//140598; provided by Applicants) in view of De Cerqueira et al (US 2015/152145; provided by Applicants) and Pizza et al., (Vaccine, 19: 2534 – 2541, 2001; provided by Applicants).
Hone discloses Mycobacterium strains (such as BCG, M. smegmatis or. M. avium) that carry a recombinant DNA sequence encoding an adjuvant (such as the A subunit of heat-labile toxin of E. coli (Elta)) to increase host immune responses, thereby improving the cancer immunotherapeutic efficacy, also in the context of treating bladder cancer (Abstract; par. 64, 77, 79, 97). However, the reference fails to disclose that the A subunit of E. coli heat-labile LT toxin is mutated.
De Cerqueira et al discloses Mycobacterium strains encoding the LT heat-labile toxin or the A subunit of the LT heat-labile toxin of E. coli mutated in position 63 from Ser to Lys. This mutation is disclosed to eliminate the ADP-ribosyltransferase activity associated with toxicity. This mutation is furthermore disclosed to maintain all the other biological properties (De Cerqueira, Abstract; par. 27).
Pizza teaches an important mutant is LTK63 (substitution of serine for lysine at position 63). They teach that this mutation eliminates the ADP-ribosyl transferase activity associated with toxicity; however, it retains all other biological properties.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use a Mycobacterium BCG strain encoding the S63K mutant of the A subunit of the LT heat-labile toxin of E. coli, for treating bladder cancer, because Hone teaches BCG strains were well-known in the prior art for treating bladder cancer and De Cerqueira and Pizza teach BCG strain with an LTK63 substitution eliminate associated toxicity while providing superior immunogenicity, a feature that would be especially important in immune comprised cancer patients.
Pertinent art, not presently relied upon:
Van Puffelen (Nature Reviews Urology volume 17 (9): pages 513–525 (July 2020) Van Puffelen et al teaches that intravesical BCG instillation is the gold-standard adjuvant immunotherapy for patients with high-risk non-muscle-invasive bladder cancer.
the improved potential of a recombinant BCG strain
for bladder cancer treatment
AUTHOR(S): Rodriguez et al
SOURCE: Frontiers in Immunology (2019), 10, 1460
CODEN: FIRMCW; ISSN: 1664-3224
URL:
DIGITAL OBJECT ID: 10.3389/fimmu.2019.01460
PUBLISHER: Frontiers Media S.A.
DOCUMENT TYPE: Journal; (online computer file)
LANGUAGE: English
ED Entered STN: 24 Jan 2020
AB The live attenuated mycobacterial strain BCG, in use as vaccine against
tuberculosis, is considered the gold std. for primary therapy of
carcinoma in situ of the bladder. Our group has developed a
recombinant BCG strain expressing the detoxified S1 pertussis toxin that
proved more effective than wild type BCG in increasing survival time in
an exptl. mouse model of bladder cancer, due to the well-known
adjuvant properties of pertussis toxin. Here, we investigated the
capacity of rBCG-S1PT to stimulate human immune responses, in comparison
to WT-BCG, using an in vitro stimulation assay based on human whole
blood cells that allows for a comprehensive evaluation of leukocyte
activation. Blood leukocytes stimulated with rBCG-S1PT produced increased
levels of IL-6, IL-8, and IL-10 as compared to WT-BCG, but comparable
levels of IL-1β, IL-2, IFN-γ, and TNF-α. PBMC stimulated
with rBCG-S1PT induced higher cytotoxicity to MB49 bladder cancer
cells than WT-BCG-stimulated PBMC. These results suggest that the
rBCG-S1PT strain is able to activate an immune response in human
leukocytes that is higher than that induced by WT-BCG for parameters
linked to better prognosis in bladder cancer (regulation of immune and
early inflammatory responses), while fully comparable to WT-BCG for
classical inflammatory parameters. This establishes rBCG-S1PT as a new
highly effective candidate as immunotherapeutic agent against bladder
cancer.
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/JENNIFER E GRASER/Primary Examiner, Art Unit 1645 8/28/26
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