DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
The amendment on May 8, 2023 is acknowledged. Claims 1-37 are canceled. Claims 38-53 are new. Claims 38-53 are subjected to examination.
Priority
The application 18/252,048 filed on May 8, 2023 claims priority from the application 371 of PCT/GB2021/052881 filed on November 5, 2021.
Information Disclosure Statement
Accordingly, the information disclosure statement (IDS) submitted on May 8, 2023 and January 10, 2024 are being considered by the examiner.
Specification
The use of the terms Nanopatch (Vaxxas, USA), SOFUSA (Kimberly- Clark, USA), Micronject600; COLOPREDICT, freeze-drying (Tolerys SA), Debioject microneedle and Micron Biomedical's dissolving microarray (see lines, 23-28; page 42), which are trade names or marks used in commerce, have been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
In addition, the lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 46 is objected to because of the following informalities: Claim 46 recites “M.w.” as a bacterial strain.
Appropriate correction is required.
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Claim Rejections - 35 USC § 112
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.
Claims 46 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
It is apparent that the Mycobacterium strains: NCTC 11659 (and associated designations SRL172, SRP299, IMM-201, DAR-90), ATCC 95051, M. paragordonae (strain 49061), M. obuense, RUTI, VPM1002BC, M. tuberculosis Aoyama B (also known as Z-100), M. indicus pranii (also known as M.w), M. brumae, M. parafortuitum, M. paratuberculosis, M. kyogaense (DSM 107316/CECT 9546), M. aurum, M. manresensis, M phlei, , BCG, SMP-105, M. smegmatis and Mycobacterium obuense NCTC 13365 are required in order to practice the invention. As such, the biological material must be readily available or obtainable by a repeatable method set forth in the specification, or otherwise readily available to the public. If it is not so obtainable or available, the requirements of 35 USC 112(a) or 35 USC 112(pre-AIA ), first paragraph may not be satisfied by a deposit of the “RUTI strain, NCTC 11659, ATCC 95051, DSM 107316/CECT 9546 and NCTC 13365” belonging to the genus Mycobacterium.
Specifically, it is noted that claim 46 recites deposited material and that claims 38-53 depend from claims reciting deposited material. The deposit of biological organisms is considered by the Examiner to be necessary for the enablement of the current invention (see 37 CRF 1.808(a)).
The process disclosed in the specification does not appear to be repeatable, it is not clear that the invention will work with commonly available material and it is not apparent if the biological materials considered necessary to make and use the invention is both known and readily available to the public.
A person skilled in the art could not make or use the invention defined in and commensurate with the claim 46 without access to the specific biological material because even though some bacteria share genomic similarities, others maintaining its distinct species, emphasizing its unique immunologic properties. Noguera-Ortega et al. (Noguera-Ortega E, Guallar-Garrido S, Julián E. Mycobacteria-Based Vaccines as Immunotherapy for Non-urological Cancers. Cancers (Basel). 2020 Jul 5;12(7):1802) pointed out that when mycobacterial agents used for the treatment of non-urological cancers are revised, it can be observed that many laboratories use the whole mycobacterium, mainly in the heat-killed form. Thus, the structural molecules located in the mycobacteria cell wall could be crucial to trigger a favorable antitumor immune response, but also could be relevant for hampering the interaction of other key antigens with the immune system. The presence of some molecules in the cell wall can disturb the immunomostimulatory capacity of antigenic mycobacterial components. For instance, the smooth morphotype of M. vaccae, which possesses a polyester in its cell wall, induces an anti-inflammatory response to compare to the pro-inflammatory profile triggered by the rough morphotype which devoids the polyester [30]. Similarly, BCG substrains differ in their capacity to trigger cytokine production in cancer or immune cells [41,50,174]. The use of different BCG substrains for non-urological cancers is worthy of mention as detailed through this review since it could influence on the reported outcomes as antitumor agent due to their different antigenic profile. Thus, the knowledge of the repertoire of antigenic compounds and their location in each species is relevant for the design of specific therapies for each type of cancer. In addition, the examiner is requesting strain type designation for all strains not well properly described in claim 46.
It is noted that Applicants have deposited biological material but there is no indication in the specification as to public availability. Therefore, a deposit at a recognized depositary may be made for to overcome this rejection.
If the deposit is made under the terms of the Budapest Treaty, then a statement, affidavit or declaration by Applicants, or by an attorney of record over his or her signature and registration number, or by someone in the position to corroborate the facts of the deposit, that the instant invention will be irrevocably and without restriction released to the public upon the issuance of a patent, would satisfy the deposit requirement made herein.
If the deposit is a non-Budapest Treaty deposit, then in order to certify that the deposit meets the requirements set forth in 37 CFR 1.801-1.809 and MPEP 2402-2411.05, a statement, affidavit or declaration by Applicant, by an attorney of record over his or her signature and registration number, or by someone in a position to corroborate the facts of the deposit would satisfy the requirements herein by stating and providing that:
(a) During the pendency of the application, access to the invention will be afforded to the Commissioner upon request;
(b) All restrictions upon availability to the public will be irrevocably removed upon granting of the patent;
(c) The deposit will be maintained in a public depositary for a period of 30 years, or 5 years after the last request or for the enforceable life of the patent, whichever is longer; and
(d) Provide evidence of the test of the viability of the biological material at the time of deposit (see 37 CFR 1.807).
Claims 38-42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim 38-42 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to a method of treating or controlling cancer comprising a primary tumour in a patient that has undergone, or is intended to undergo, tumour resection surgery, administering to the subject, a non-pathogenic non-viable Mycobacterium, tumour resection surgery, and one or more additional anticancer treatments or agents wherein said method results in enhanced therapeutic efficacy relative to administration of non-pathogenic non-viable Mycobacterium. The method results in subtotal regression as demonstrated by less than 10% vital tumour cells present in tumour biopsy or resected tumours, stable disease (SD), a complete response (CR) or partial response (PR) of the primary tumour; and/or stable disease (SD) or complete response (CR) of one or more non-target tumours, as assessed by Immune Related Response Criteria (irRC), iRECIST, RECIST 1.1, or irRECIS. The method results in reducing or inhibiting formation or establishment of metastases arising from a primary tumour or cancer to one or more other sites, locations or regions distinct from the primary tumour or cancer; reducing or inhibiting growth or proliferation of a metastasis at one or more other sites, locations or regions distinct from the primary tumour or cancer after a metastasis has formed or has been established, reducing or inhibiting formation or establishment of additional metastasis after the metastasis has been formed or established, prolonged overall survival, prolonged progression free survival, (6) disease stabilisation, increased quality of life, and combinations thereof.
Claim 38 is drawn to a method of treating or controlling a primary tumor in a patient that has undergone, or is intended to undergo, tumor resection surgery comprising to the subject, a non-pathogenic non-viable Mycobacterium, tumor resection surgery, and one or more additional anticancer treatments or agents. The dependent claims state that the cancer is selected from the group consisting of bladder cancer, prostate cancer, liver cancer, renal cancer, lung cancer, breast cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, brain cancer, hepatocellular cancer, lymphoma, leukaemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer, melanoma, head and neck cancer, skin cancer and soft tissue sarcoma and/or osteosarcoma, pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors.
The claims 38-42 broadly encompass all forms of cancers, however the specification does not teach the treatment of all the forms of cancers said to be treatable by the applicant’s method. The applicability of method to all types of cancers asserted in the claims mentioned above is unknown and/or not readily reproducible by the artesian. In the specification, the applicant disclaims that “The present invention provides a protocol to use IMM-101 as a surprisingly favourable neoadjuvant treatment, or adjuvant treatment, with or without the use of other chemotherapy agents, to improve the unfavourable prognosis of patients intended to undergo tumour resection surgery or checkpoint inhibitor therapy for cancer. Such patients may include those with colorectal cancer, particularly mismatch repair-deficient (dMMR) colorectal cancers with microsatellite instability (MSI)” (see specification; page 14). However, there is also uncertainty regarding to the use of the method for the form of cancer mentioned above. Thus, one of skill in the art would not readily recognize the use of the method to treat all forms of cancers claimed by the applicant if there is a lack of written description of method and use of the genus (types/forms of cancer) in the claims. The written description requirement is not fulfilled by the applicant.
In order to comply with the written description requirement, the applicant must fully disclosure all forms of cancers claimed to be treatable by the applicant’s invention regarding the protocol of use of the method for all forms/types of cancer in specifications.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Thus, the method recited in claim 38 must be able to treat and/or control any forms of cancer recited in claims 38-42. It is apparent that there is no written description in the specification showing that the method comprising the administration of non-pathogenic non-viable Mycobacterium strain(s) and additional anticancer agents and treatments, including resection surgery is capable of treating or controlling each of the cancer forms claimed in the invention. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. In the specification, there is no clear disclosure of each form/type of cancers have been treated or controlled using the method claimed in the invention. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Figures 1 and 2 are directed to schematics of a clinical trial investigations. The only mention of colorectal cancer is regarding high/dMMR (Mismatch repair-deficient (dMMR) with microsatellite instability patients) the skilled artisan cannot envision the detailed method of treating or controlling any forms of cancer encompassed in claim 38-42, specially because adequate written description requires more than a mere statement that it is part of the invention and reference to administrating non-pathogenic non-viable Mycobacterium strain, one or more additional anticancer treatments or agents and tumor resection. Noguera-Ortega et al. (Noguera-Ortega E, Guallar-Garrido S, Julián E. Mycobacteria-Based Vaccines as Immunotherapy for Non-urological Cancers. Cancers (Basel). 2020 Jul 5;12(7):1802) discloses the use of IMM-101 (Mycobacterium obuense NCTC 13365) first for priming before tumor challenge, and later as a subcutaneous therapeutic agent in colorectal mouse models, showed a significant reduction in the number of lung metastatic lesions. However, IMM-101 on its own administered subcutaneously as therapy had no significant effect on tumor growth [81]. Some clinical trials demonstrated the efficacy of repeated injections (up to a year) of IMM-101 in colorectal cancer (NCT03009058). In combination with radiation in metastatic colorectal patients in which other therapies were not effective, no synergy was observed (NCT01539824).
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2dl961,1966 (1997); In re Gosteli, 872 F.2dl008,1012,10 USPQ2dl614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d.
Accordingly, the disclosure is not commensurate with the scope of the claim. Claim 42 encompass a group of types/forms of cancers wherein a cancer selected from that group is treated by using the method in claim 38. There is no evidence that the method comprising administration of a non-pathogenic non-viable Mycobacterium, administration of one or more additional anticancer treatments or agents, or tumor resection surgery alone is therapeutically effective for treating all forms of the cancer in claim 42.
Further, the state of art discloses that Noguera-Ortega et al. (Noguera-Ortega E, Guallar-Garrido S, Julián E. Mycobacteria-Based Vaccines as Immunotherapy for Non-urological Cancers. Cancers (Basel). 2020 Jul 5;12(7):1802) pointed out that the whole cells of M. vaccae, M. obuense, MIP, M. smegmatis, and BCG have been studied for melanoma. SRL172 showed a positive correlation between longer survival and intracellular IL-2 detection in peripheral blood lymphocytes when used as antitumor agent for the treatment of stage IV melanoma patients [78]. Noguera-Ortega et al. discloses a clinical trial (NCT) was performed administering an SRL172 plus IL-2 combination therapy, but only three partial remissions were observed in a total of 16 patients. Thus, no therapeutic effect was established [79]. Nevertheless, a retrospective study concluded that this treatment could be effective in lower grade melanoma patients [80]. M. obuense was unsuccessfully used in two clinical trials. Although IMM-101 (Mycobacterium obuense NCTC 13365) had a positive effect on avoiding metastasis in a melanoma mouse model, it showed no effect on the overall tumor burden (NCT01559818, NCT01559819) [81]. Furthermore, in a small clinical trial with advanced melanoma, patients tolerated the therapy, but only 15% of clinical responses were observed (NCT01308762) [82]. Recently, immune checkpoint inhibitors have become the standard of care for melanoma patients, as they show the highest long-term survival of patients with metastatic melanoma that has ever seen with any other therapy, although high levels of toxicity have been observed. Dalgleish and collaborators, in a small clinical trial, showed it was more efficacious without added toxicity when combining IMM-101 and checkpoint inhibitors [83].
Yet, Noguera-Ortega et al. (Noguera-Ortega E, Guallar-Garrido S, Julián E. Mycobacteria-Based Vaccines as Immunotherapy for Non-urological Cancers. Cancers (Basel). 2020 Jul 5;12(7):1802) recites the phase III trial on a cohort of more than 400 non-small cell lung cancer (NSCLC) patients confirmed that SRL172 led to the improvement in the quality of life of the patients, but without any improvement on overall survival [108]. However, the number of intradermal SRL172 injections was very variable between patients in this study. When the data obtained were re-analyzed taking into account the histological lung tumor type and the number of adjuvant inoculations, adenocarcinoma patients, but not squamous cell carcinoma patients, survived significantly longer when receiving combination therapy [109].
Monk et al. (Monk BJ, Enomoto T, Kast WM, McCormack M, Tan DSP, Wu X, González-Martín A. Integration of immunotherapy into treatment of cervical cancer: Recent data and ongoing trials. Cancer Treat Rev. 2022 May; 106:102385) disclose the use of Z-100, an immunomodulatory extract from Mycobacterium tuberculosis strain Aoyama B used in Japan to treat leukopenia resulting from radiotherapy [67]. In an earlier placebo-controlled, phase III trial of Z-100 in combination with radiotherapy or CRT (collectively referred to as RT) for patients with stage IIB-IVA cervical cancer, Z-100 did not provide a statistically significant improvement of 5-year overall survival (OS) compared with placebo (75.7% vs 65.8%; HR, 0.65, P = 0.07), and did not differ in recurrence-free survival [70]. However, there was an OS benefit for patients with stage III disease treated with Z-100 (HR, 0.51; P = 0.03). A phase III, placebo-controlled trial of Z-100 plus radiotherapy for patients with treatment-naïve stage IIIB (FIGO 2008) locally advanced cervical cancer (LACC) was initiated in December 2014. The study is being conducted in seven countries within Asia. The trial has completed enrollment and the expected date for primary endpoint completion (OS) was October 2021. Published results are anticipated.
Even though, there is an overall survival (OS) benefit for phase III trial of Z-100 in combination with radiotherapy or CRT (collectively referred to as RT) for patients with stage IIB-IVA cervical cancer, Z-100 did not provide a statistically significant improvement of 5-year overall survival (OS) compared with placebo (75.7% vs 65.8%; HR, 0.65, P = 0.07), and did not differ in recurrence-free survival.
Therefore, neither the art nor the specification provide a representative number of cancers that can be controlled or treated by the claim invention.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim 47 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim 47 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claim is drawn to a method of treating cancer comprising administering to the subject the non-pathogenic non-viable Mycobacterium obuense strain NCTC 13365 or a fraction, fragment, sub-cellular component, lysate, homogenate, sonicate, or substantially in whole cell form. The method further recites other non-pathogenic non-viable Mycobacterium selected from a group of strains listed in claim 46. The method recites a combination of several well-known anticancer treatments including adoptive cell, surgical therapy, chemotherapy and radiation with the mycobacterial strains recited in claim 46 and 47. Alternatively, claim 47 also recites the use of a “fraction, fragment, sub-cellular component, lysate, homogenate, sonicate, or substantially in whole cell form in combination with the additional cancer methods recited in claim 46.
The specification teaches “the non-pathogenic non-viable Mycobacterium is the rough variant and/or a presented as a fraction, fragment, sub-cellular component, lysate, homogenate, sonicate, or substantially in whole cell form, such as where more than 50% or more of the mycobacteria in suspension are greater than 1 to 10 microns in diameter, as measured by laser diffraction (e.g. D50 value or mean particle size), or is in a form which has not been exposed to high pressure processing or other conditions to induce substantial cell lysis” (see lines 4-9; page 16). It also teaches “As would be understood by the skilled person, rough variants of M. obuense, for example, would lack cell surface-associated glycopeptidolipids (GPL) resulting in a characterised rough morphology with non-motile and non-biofilm-forming properties, as described in Roux et al. 2016, Open Biol 6: 160185. The amount of Mycobacterium administered to the patient in the present invention would be sufficient to elicit a protective immune response in the patient such that the patient's immune system would be able to mount an effective immune response” (See lines 10-16; page 16). However, the specification does not clarify or describe each one of the components recited in the claim 47 used to treat cancer in the art. E.g. a fragment could be from cell membrane, nucleus, proteins, nucleic acids, etc. The same applies for the term “substantially in the whole form, since substantially does not describe amount or asserts specific parts in the subject, whole cell. The written description encompasses several genus and there is no structural description as to what portion of the bacteria is claimed in the invention.
Bacteria are unicellular organisms comprised with several different structures that can vary depending on the strain. E.g., cell wall, membrane, cytoplasm, outer membrane, capsule, genetic material and ribosomes. However, even though the applicant recites the Mycobacterium variants and its cellular/morphological differences in the specification it does not describe “a fraction, fragment, sub-cellular component, lysate, homogenate, sonicate, or substantially in whole cell form” or the methods of making the non-viable bacterial strain recited in claim 47 used to treat cancer.
"Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled in the art would not conclude which “fraction, fragment, sub-cellular component, lysate, homogenate, sonicate, or substantially in whole cell form from the Mycobacterium is actually used for the method in claim 47. In addition, there is minimal written description on how to obtain the subjects in claim 47. It does appear to be a written description of the limitation in the specification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
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.
Claims 38 and 53 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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. Claims 38 and 53 are generally narrative and indefinite, failing to conform with the current U.S. practice.
Claim 38 is indefinite for the recitation of “controlling” cancer because it implies that the method claimed is able to modulated cancer to either be increased or decreased, or at least tuned. Therefore, the recitation is interpreted as an intended treatment thus the metes and bounds of the claim is unclear.
Claim 38 also recites “intend” to undergo as possibility of an event, such as tumour resection surgery. However, the term is unclear or vague.
Claim 53 is indefinite for the recitation of a “sub-therapeutic” amount and/or duration. The specification defines " means a dose of a therapeutic compound10 (e.g., antibody) or duration of therapy which is lower than the usual or typical dose of the therapeutic compound or therapy of shorter duration, when administered alone for the treatment of cancer. Typical doses of known therapeutic compounds are known to those skilled in the art or can be determined through routine experimental work (Page 9; line 9). Sub-therapeutic as A “sub-therapeutic dose” is being used as definition of amount/dose and time. However, the term “sub-therapeutic” is unclear.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 38-47, 49 and 50-51 are rejected under 35 U.S.C. 102(a) as being anticipated by Costa Neves et al. (Published December 26, 2015; hereafter Costa Neves; PTO-892).
Claim 38 is drawn to a method of treating or controlling cancer comprising a primary tumour in a patient that has undergone, or is intended to undergo, tumour resection surgery, wherein said method comprises simultaneously, separately or sequentially administering to the subject, (i) a non-pathogenic non-viable Mycobacterium, (ii) tumour resection surgery, and (iii) one or more additional anticancer treatments or agents, wherein said method results in enhanced therapeutic efficacy relative to administration of non-pathogenic non-viable Mycobacterium, administration of one or more additional anticancer treatments or agents, or tumour resection surgery alone.
Claim 39 is drawn to the method according to claim 38, wherein said method results results in: subtotal regression as demonstrated by less than 10% vital tumour cells present in tumour biopsy or resected tumours, stable disease (SD), a complete response (CR) or partial response (PR) of the primary tumour; and/or stable disease (SD) or complete response (CR) of one or more non-target tumours, as assessed by Immune Related Response Criteria (irRC), iRECIST, RECIST 1.1, or irRECIST.
Claim 40 is drawn to the method according to claim 39, wherein said method results in (1), reducing or inhibiting formation or establishment of metastases arising from a primary tumour or cancer to one or more other sites, locations or regions distinct from the primary tumour or cancer; (2) reducing or inhibiting growth or proliferation of a metastasis at one or more other sites, locations or regions distinct from the primary tumour or cancer after a metastasis has formed or has been established, (3) reducing or inhibiting formation or establishment of additional metastasis after the metastasis has been formed or established, (4) prolonged overall survival, (5) prolonged progression free survival, (6) disease stabilisation, (7) increased quality of life, and combinations thereof.
Claim 41 is drawn to the method according to claim 38, wherein said one or more additional anticancer treatments or agents is selected from adoptive cell therapy, surgical therapy, chemotherapy, radiation therapy, hormonal therapy, checkpoint inhibitor therapy, small molecule therapy, receptor kinase inhibitor therapy, hyperthermia treatment, phototherapy, radiofrequency ablation therapy (RFA), anti-angiogenic therapy, cytokine therapy, cryotherapy, biological therapy, HDAC inhibitor, BRAF inhibitor, MEK inhibitor, EGFR inhibitor, VEGF inhibitor, P13K delta inhibitor, PARP inhibitor, mTOR inhibitor, hypomethylating agents, oncolytic virus, TLR agonists, STING agonists, mifamurtide, cancer vaccines, and combinations thereof.
Claim 42 is drawn to the method according to claim 38, wherein the cancer is selected from the group consisting of bladder cancer, prostate cancer, liver cancer, renal cancer, lung cancer, breast cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, brain cancer, hepatocellular cancer, lymphoma, leukaemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer, melanoma, head and neck cancer, skin cancer and soft tissue sarcoma and/or osteosarcoma, pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumours (PNET).
Claim 43 is drawn to the method according to claim 42, wherein said cancer is metastatic.
Claim 44 is drawn to the method according to claim 38, wherein said cancer is clinically defined by a TNM staging criteria, in which the patient has a primary tumour (T) of T1 to T4, and/or a Node designation of N0, N1 or N2, or wherein said cancer is clinically defined as being Stage I, Stage II or Stage III.
Claim 45 is drawn to the method according to claim 44, wherein said patient has no evidence of metastasis (MO), as defined by a TNM staging criteria.
Claim 46 is drawn to the method according to claim 38, wherein non-pathogenic non-viable Mycobacterium is selected from M vaccae, the strain deposited under accession number NCTC 11659 and associated designations SRL172, SRP299, IMM-201, DAR-901, and the strain as deposited under ATCC 95051; M. obuense, M. paragordonae (strain 49061), M parafortuitum, M.paratuberculosis, M brumae, M. aurum, M. indicus pranii, M.w, M. manresensis, M. kyogaense (as deposited under DSM 107316/CECT 9546), M phlei, M. smegmatis, M. tuberculosis Aoyama B or H37Rv, RUTI, BCG, VPM1002BC, SMP-105, Z-100, the strain of Mycobacterium obuense deposited under the Budapest Treaty under accession number NCTC 13365 and combinations thereof.
Claim 47 is drawn to the method according to claim 46, wherein the non-pathogenic non-viable Mycobacterium is M obuense NCTC 13365 or a fraction, fragment, sub-cellular component, lysate, homogenate, sonicate, or substantially in whole cell form.
Claim 49 is drawn to the method according to claim 38, wherein the immunomodulator is administered prior to tumour resection surgery and/or administration of said one or more additional anticancer treatments or agents for at least 1 to 3 doses or for 3 doses.
Claim 50 is drawn to the method according to claim 38, wherein the immunomodulator is administered following tumour resection surgery or administration of said one or more additional anticancer treatments or agents optionally wherein said administration is over a period of 12 months or more.
Claim 51 is drawn to the method according to claim 38, wherein said one or more agents are selected from: bevacizumab, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, cisplatin, epirubicin, capecitabine, leucovorin, folinic acid, carboplatin, oxaliplatin, gemcitabine, FOLFIRINOX, FOLFOX, mFOLFIRINOX, NALIRIFOX, paclitaxel, nab-paclitaxel, pemetrexed, irinotecan, temozolomide and combinations thereof, wherein said one or more additional anticancer treatments or agents is administered intratumorally, intraarterially, intravenously, intravascularly, intrapleuraly, intraperitoneally, intratracheally, intranasally, pulmonarily, intrathecally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, regionally, stereotactically, orally or by direct injection or perfusion.
As to claims 38-47, 49 and 50-51, Costa Neves teaches a method of treating comprising resection of primary tumor (pancreatoduodenectomy) and metastatic site (left hepatectomy), anticancer agents such as gemcitabine and nab-paclitaxel and administration of a non-pathogenic Mycobacterium obuense (NCTC13365). Costa Neves teaches a complete pathological regression of both primary pancreatic and metastatic disease. Costa Neves teaches the maintenance of performance status in the face of prolonged chemotherapy exposure, permitted by the use of an unconventional low dose rather than the maximum tolerated dosing schedule. Costa Neves teaches that IMM-101 is a suspension of heat-killed whole cell Mycobacterium obuense (NCTC13365) administered by intradermal injection. Costa Neves teaches a treatment of a patient with pancreatic cancer (PDAC) comprising chemotherapy, IMM-101 and gemcitabine. Costa Neves teaches that a CT scan showed a partial response in the dimensions of both the primary and liver sites, according to RECIST criteria. Costa Neves teaches nab-paclitaxel was added to the gemcitabine and IMM101 combination. The patient demonstrated an excellent and sustained partial response for the following six cycles. Costa Neves teaches that following completion of radiotherapy, capecitabine and IMM-101 were continued as maintenance therapy. Costa Neves teaches that four months after chemoradiotherapy, an FDG-PET scan showed no avidity in either the primary tumor or the liver. Costa Neves teaches that the patient was diagnosed with a staging T4N1M0 pancreas cancer and that after treatment the main pancreatic duct and its major branches exhibited active lympho-histiocytic infiltration with a predominance of lymphocytes - pathological stage was ypT0 N0 (0/11) M0 V0. Costa Neves teaches that in view of the patient’s exceptional response and following discussion in a multidisciplinary meeting, it was agreed to re-attempt resection. Twenty-two months after patient’s initial diagnosis and six weeks after completion of chemoradiation, the patient underwent pylorus-preserving pancreatoduodenectomy with portal vein resection, left hepatectomy, and coeliac and retroperitoneal nodal dissection. Costa Neves teaches that postoperatively, the patient continued to receive IMM-101 and restarted capecitabine ten weeks after the operation. At twelve months from surgery, a CT scan showed bilateral small volume lung metastases and a further solitary lesion in the liver. She subsequently received radiofrequency ablation to both lungs, stereotactic radiation to the liver, and restarted gemcitabine + nab-paclitaxel following the development of a malignant pleural effusion. Costa Neves teaches that the patient maintains a good quality of life and has sustained the ECOG PS of 1 almost four years from diagnosis of her metastatic PDAC.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 38-47, 49 and 50-51, Claims 48 and 52-53 are rejected under 35 U.S.C. 103 as being unpatentable over Costa Neves et al. (Published December 26, 2015; hereafter Costa Neves; PTO-892) in view of Biot et al. (EP-2620159-A1; hereafter Biot; PTO-892).
Claim 38 is drawn to a method of treating or controlling cancer comprising a primary tumour in a patient that has undergone, or is intended to undergo, tumour resection surgery, wherein said method comprises simultaneously, separately or sequentially administering to the subject, (i) a non-pathogenic non-viable Mycobacterium, (ii) tumour resection surgery, and (iii) one or more additional anticancer treatments or agents, wherein said method results in enhanced therapeutic efficacy relative to administration of non-pathogenic non-viable Mycobacterium, administration of one or more additional anticancer treatments or agents, or tumour resection surgery alone.
Claim 39 is drawn to the method according to claim 38, wherein said method results results in: subtotal regression as demonstrated by less than 10% vital tumour cells present in tumour biopsy or resected tumours, stable disease (SD), a complete response (CR) or partial response (PR) of the primary tumour; and/or stable disease (SD) or complete response (CR) of one or more non-target tumours, as assessed by Immune Related Response Criteria (irRC), iRECIST, RECIST 1.1, or irRECIST.
Claim 40 is drawn to the method according to claim 39, wherein said method results in (1), reducing or inhibiting formation or establishment of metastases arising from a primary tumour or cancer to one or more other sites, locations or regions distinct from the primary tumour or cancer; (2) reducing or inhibiting growth or proliferation of a metastasis at one or more other sites, locations or regions distinct from the primary tumour or cancer after a metastasis has formed or has been established, (3) reducing or inhibiting formation or establishment of additional metastasis after the metastasis has been formed or established, (4) prolonged overall survival, (5) prolonged progression free survival, (6) disease stabilisation, (7) increased quality of life, and combinations thereof.
Claim 41 is drawn to the method according to claim 38, wherein said one or more additional anticancer treatments or agents is selected from adoptive cell therapy, surgical therapy, chemotherapy, radiation therapy, hormonal therapy, checkpoint inhibitor therapy, small molecule therapy, receptor kinase inhibitor therapy, hyperthermia treatment, phototherapy, radiofrequency ablation therapy (RFA), anti-angiogenic therapy, cytokine therapy, cryotherapy, biological therapy, HDAC inhibitor, BRAF inhibitor, MEK inhibitor, EGFR inhibitor, VEGF inhibitor, P13K delta inhibitor, PARP inhibitor, mTOR inhibitor, hypomethylating agents, oncolytic virus, TLR agonists, STING agonists, mifamurtide, cancer vaccines, and combinations thereof.
Claim 42 is drawn to the method according to claim 38, wherein the cancer is selected from the group consisting of bladder cancer, prostate cancer, liver cancer, renal cancer, lung cancer, breast cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, brain cancer, hepatocellular cancer, lymphoma, leukaemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer, melanoma, head and neck cancer, skin cancer and soft tissue sarcoma and/or osteosarcoma, pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumours (PNET).
Claim 43 is drawn to the method according to claim 42, wherein said cancer is metastatic.
Claim 44 is drawn to the method according to claim 38, wherein said cancer is clinically defined by a TNM staging criteria, in which the patient has a primary tumour (T) of T1 to T4, and/or a Node designation of N0, N1 or N2, or wherein said cancer is clinically defined as being Stage I, Stage II or Stage III.
Claim 45 is drawn to the method according to claim 44, wherein said patient has no evidence of metastasis (MO), as defined by a TNM staging criteria.
Claim 46 is drawn to the method according to claim 38, wherein non-pathogenic non-viable Mycobacterium is selected from M vaccae, the strain deposited under accession number NCTC 11659 and associated designations SRL172, SRP299, IMM-201, DAR-901, and the strain as deposited under ATCC 95051; M. obuense, M. paragordonae (strain 49061), M parafortuitum, M.paratuberculosis, M brumae, M. aurum, M. indicus pranii, M.w, M. manresensis, M. kyogaense (as deposited under DSM 107316/CECT 9546), M phlei, M. smegmatis, M. tuberculosis Aoyama B or H37Rv, RUTI, BCG, VPM1002BC, SMP-105, Z-100, the strain of Mycobacterium obuense deposited under the Budapest Treaty under accession number NCTC 13365 and combinations thereof.
Claim 47 is drawn to the method according to claim 46, wherein the non-pathogenic non-viable Mycobacterium is M. obuense NCTC 13365 or a fraction, fragment, sub-cellular component, lysate, homogenate, sonicate, or substantially in whole cell form.
Claim 48 is drawn to the method according to claim 38, wherein the immunomodulator is administered in a dose comprising 103-109 cells, or 0.0001 to 1.0 mg.
Claim 49 is drawn to the method according to claim 38, wherein the immunomodulator is administered prior to tumour resection surgery and/or administration of said one or more additional anticancer treatments or agents for at least 1 to 3 doses or for 3 doses.
Claim 50 is drawn to the method according to claim 38, wherein the immunomodulator is administered following tumour resection surgery or administration of said one or more additional anticancer treatments or agents optionally wherein said administration is over a period of 12 months or more.
Claim 51 is drawn to the method according to claim 38, wherein said one or more agents are selected from: bevacizumab, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, cisplatin, epirubicin, capecitabine, leucovorin, folinic acid, carboplatin, oxaliplatin, gemcitabine, FOLFIRINOX, FOLFOX, mFOLFIRINOX, NALIRIFOX, paclitaxel, nab-paclitaxel, pemetrexed, irinotecan, temozolomide and combinations thereof, wherein said one or more additional anticancer treatments or agents is administered intratumorally, intraarterially, intravenously, intravascularly, intrapleuraly, intraperitoneally, intratracheally, intranasally, pulmonarily, intrathecally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, regionally, stereotactically, orally or by direct injection or perfusion.
Claim 52 is drawn to the method according to claim 38, wherein said administration of one or more additional anticancer treatments or agents is a checkpoint inhibitor therapy selected from ipilimumab, nivolumab, pembrolizumab, azetolizumab, BI 754091 (anti-PD-1), bavituximab, bintrafusp alfa, durvalumab, dostarlimab, tremelimumab, spartalizumab, avelumab, sintilimab, toripalimab, prolgolimab, tislelizumab, camrelizumab, MGA012, MGD013(tebotelimab), MGD019, enoblituzumab, MGD009, MGC018, MEDI0680, miptenalimab, nimotuzumab, PDR001, FAZ053, TSR022, MBG453, relatlimab (BMS986016), LAG525 (IMP701), IMP321 (Eftilagimod alpha), REGN2810 (cemiplimab), REGN3767, pexidartinib, LY3022855, FPA008, BLZ945, GDC0919, epacadostat, emactuzumab, FPA150, indoximid, BMS986205, CPI-444, MEDI9447, PBF509, FS 118, lirilumab, Sym023, TSR-022, A2Ar inhibitors, NKG2A, and combinations thereof.
Claim 53 is drawn to the method according to claim 52, wherein one or more checkpoint inhibitors are each administered in a sub-therapeutic amount and/or duration.
The instant claims are directed to a method of treating or controlling cancer wherein the immunomodulator is administered in a dose comprising 103-109 cells, or 0.0001 to 1.0 mg. The method wherein said administration of one or more additional anticancer treatments or agents is a checkpoint inhibitor therapy selected from ipilimumab, nivolumab, pembrolizumab, azetolizumab, BI 754091 (anti-PD-1), bavituximab, bintrafusp alfa, durvalumab, dostarlimab, tremelimumab, spartalizumab, avelumab, sintilimab, toripalimab, prolgolimab, tislelizumab, camrelizumab, MGA012, MGD013(tebotelimab), MGD019, enoblituzumab, MGD009, MGC018, MEDI0680, miptenalimab, nimotuzumab, PDR001, FAZ053, TSR022, MBG453, relatlimab (BMS986016), LAG525 (IMP701), IMP321 (Eftilagimod alpha), REGN2810 (cemiplimab), REGN3767, pexidartinib, LY3022855, FPA008, BLZ945, GDC0919, epacadostat, emactuzumab, FPA150, indoximid, BMS986205, CPI-444, MEDI9447, PBF509, FS 118, lirilumab, Sym023, TSR-022, A2Ar inhibitors, NKG2A, and combinations thereof. The method according to claim 52, wherein one or more checkpoint inhibitors are each administered in a sub-therapeutic amount and/or duration.
Costa Neves teaches a method of treating cancer comprising resection of primary tumor (pancreatoduodenectomy) and metastatic site (left hepatectomy), anticancer agents such as gemcitabine and nab-paclitaxel and administration of a non-pathogenic Mycobacterium obuense (NCTC13365). Costa Neves teaches a complete pathological regression of both primary pancreatic and metastatic disease. Costa Neves teaches the maintenance of performance status in the face of prolonged chemotherapy exposure, permitted by the use of an unconventional low dose rather than the maximum tolerated dosing schedule. Costa Neves teaches that IMM-101 is a suspension of heat-killed whole cell Mycobacterium obuense (NCTC13365) administered by intradermal injection. Costa Neves teaches a treatment of a patient with pancreatic ductal adenocarcinoma cancer (PDAC) comprising chemotherapy, IMM-101 and gemcitabine. Costa Neves teaches that a CT scan showed a partial response in the dimensions of both the primary and liver sites, according to RECIST criteria. Costa Neves teaches nab-paclitaxel was added to the gemcitabine and IMM101 combination. The patient demonstrated an excellent and sustained partial response for the following six cycles. Costa Neves teaches that following completion of radiotherapy, capecitabine and IMM-101 were continued as maintenance therapy. Costa Neves teaches that four months after chemoradiotherapy, an FDG-PET scan showed no avidity in either the primary tumor or the liver. Costa Neves teaches that the patient was diagnosed with a staging T4N1M0 pancreatic cancer and that after treatment the main pancreatic duct and its major branches exhibited active lympho-histiocytic infiltration with a predominance of lymphocytes - pathological stage was ypT0 N0 (0/11) M0 V0. Costa Neves teaches that in view of the patient’s exceptional response and following discussion in a multidisciplinary meeting, it was agreed to re-attempt resection. Twenty-two months after patient’s initial diagnosis and six weeks after completion of chemoradiation, the patient underwent pylorus-preserving pancreatoduodenectomy with portal vein resection, left hepatectomy, and coeliac and retroperitoneal nodal dissection. Costa Neves teaches that postoperatively, the patient continued to receive IMM-101 and restarted capecitabine ten weeks after the operation. At twelve months from surgery, a CT scan showed bilateral small volume lung metastases and a further solitary lesion in the liver. She subsequently received radiofrequency ablation to both lungs, stereotactic radiation to the liver, and restarted gemcitabine + nab-paclitaxel following the development of a malignant pleural effusion. Costa Neves teaches that the patient maintains a good quality of life and has sustained the ECOG PS of 1 almost four years from diagnosis of her metastatic PDAC.
Costa Neves does not teach the immunomodulator (non-pathogenic non-viable Mycobacterium) is administered in a dose comprising 103-109 cells, or 0.0001 to 1.0 mg. Costa Neves teaches does not teach a checkpoint inhibitor therapy nor does Costa Neves in a sub-therapeutic amount and/or duration.
Biot teaches a method for treating cancer comprising administering non-pathogenic mycobacteria, which “the dose of live nonpathogenic mycobacteria in the composition depends on the age of the patients. For human adults, it is in the range of 107 to 1010 CFUs (Colony Forming Units) for the local and parenteral or oral administrations, preferably about 108 to 109 CFUs. The dose of killed non-pathogenic mycobacteria in the composition is in the range of 50 to 150 mg, which corresponds to the amount of killed mycobacteria obtained starting with 109 to 1011 CFUs before the killing. The dose of mycobacterial cell wall fraction is in the range of 1 to 10 mg, preferably formulated in an emulsion.” [0030].
Biot teaches a method for treating cancer comprising a non-pathogenic mycobacteria or immunogenic component(s) thereof may be used in combination (separate or sequential use) with such additional agents such as pro-inflammatory agents such as inflammatory cytokines and blocking antibodies directed against T-cell negative co-stimulatory molecules also known as checkpoint inhibitors (CTLA-4, PD-1, TIM-3, BTLA, VISTA, LAG-3), antibiotics and chemotherapy drugs. “The composition(s) for use in the present invention may further comprise one or more additional agents like : (i) pro-inflammatory agents such as inflammatory cytokines (IL-2, IFN-α, TNF-α, GM-CSF), (ii) T-cell stimulatory molecules such as agonist antibodies directed against T-cell activating co-stimulatory molecules (CD28, CD40, OX40, GITR, CD137, CD27, HVEM) and blocking antibodies directed against T-cell negative co-stimulatory molecules (CTLA-4, PD-1, TIM-3, BTLA, VISTA, LAG-3), (iii) antibiotics, and (iv) chemotherapy drugs [0031]”. Alternatively, the composition (s) comprising a non-pathogenic mycobacteria or immunogenic component(s) thereof may be used in combination (separate or sequential use) with such additional agents [0032].
Biot also teaches that the route of administration, the type of mammal (human or animal) being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors, that those skilled in the medical arts will recognize. The pharmaceutically effective dose depends upon the composition used, the route of administration, the type of mammal (human or animal) being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors, that those skilled in the medical arts will recognize” [0030].
Biot teaches a method comprising administration of non-pathogenic non-viable Mycobacterium strain and anticancer treatments or agents and tumor resection surgery to treat cancer and discloses the range dose of non-pathogenic non-viable Mycobacterium strain administered to the subject and the use of checkpoint blockers in the method. Biot also disclaims that the dose of use and/or duration of anticancer agents and therapy depends of several factors such as route of administration, the type of mammal (human or animal) being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors, that those skilled in the medical arts will recognize.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to combine the method of Biot to the method of Costa Neves, because Biot teaches the dose range of non-pathogenic Mycobacterium administered to the subject and the use of adjustable doses of checkpoint inhibitors can be applied to treat cancer. It would be expected, absent evidence to the contrary, that use of the method of Biot with the same method as Costa Neves, which is known to treat cancer, would produce the desired disease treatment. The advantages of checkpoint blockers known to treat several forms of cancer disease provides the motivation to make the aforementioned modification of the method of Costa Neves, based on the teachings of an effective anticancer drugs and checkpoint inhibitors directed against T-cell negative costimulatory molecules as taught by Biot, with a reasonable expectation of success.
Furthermore, the use of the method of treating cancer of Biot would be a known variation in the art that could be reasonably applied to the method of Costa Alves by one of skill in the art. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The method of Biot recites the use of checkpoint blockers in combination with non-pathogenic Mycobacterium and other anticancer therapies, and because Costa Alves specifically recognizes the potential of treatment effect of the administration of M. obuense (NCTC 13365) and anticancer therapy and agents such as gemcitabine and nab-paclitaxel for cancer, applying the methods of Biot to the patient of Costa Neves would be encompassed in a known variation of principle in the art. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Conclusion
No claims are allowed.
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/PRICILA NMN HAUK TEODORO/Examiner, Art Unit 1645
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674