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 .
DETAILED ACTION
Priority
Acknowledgment is made of applicant's claim for foreign priority based on applications GB2017554.3 and GB2104427.6, respectively filed in November 6, 2020 and March 29, 2021 on United Kingdom of Great Britain and North Ireland.
Information Disclosure Statement
The information disclosure statements (IDS) submitted have been considered by the examiner.
Status of applications, Amendments, and/or Claims
The Response filed 6 July 2026 has been entered in full. Claims 1-37, 42-44, 46-47, 49 have been canceled without prejudice or disclaimer, and claims 38, 45, 48, 50, 53 have been currently amended. Claims 54-55 are new. Therefore, claims 38-41, 45, 48, 50-55 are the subjected of this Office Action.
Withdrawn Objections and/or Rejections
The objection to the specification is withdrawn in view of applicant’s corrections.
The objection to claim 46 is withdrawn in view of Applicant’s cancellation of the claim.
The rejection of claims 38-42 on the ground of 35 U.S.C 112 (a) as failing to comply with the written description requirement as set forth at pp. 7-17 are withdrawn in view of Applicant’s amendments or cancellation of the claims.
The rejection of claim 46 on the ground of 35 U.S.C 112 (a) as failing to comply with the enablement requirement as set forth at pp. 4-6 is withdrawn in view of Applicant’s cancellation of the claims.
The rejection of claims 38, 53 on the ground of 35 U.S.C 112 (b) as failing to conform with the current U.S practice as set forth at pp. 17-18 is withdrawn in view of Applicant’s amendments to the claims.
The rejection of claims 38-47, 49, 50-51 on the ground of 35 U.S.C 102 rejection as set forth at pp. 18-23 are withdrawn in view of Applicant’s amendments or cancellation of the claims.
New Claim Rejections - 35 USC § 112
Necessitated by Amendment
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 38 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. This rejection has been reintroduced and made newly in view of applicant’s amendments to claim 38. 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. This is an enablement rejection.
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 38 recites deposited material and that claims 38-41, 45, 48, 50-55 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.
Further, a person skilled in the art could not make or use the invention defined in and commensurate with the claim 38 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 38.
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 38-41, 45, 48, 50-55 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. This is a written description rejection. Claims 38-41, 45, 48, 50-55 contain 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.
Claim 38 is drawn to a method of treating cancer comprising a primary tumour in a patient that has undergone, or is undergoing a neoadjuvant, perioperative, or adjuvant protocol for 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, 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, 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), 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 NO, N1 or N2, or wherein said cancer is clinically defined as being Stage I, Stage II or Stage III, wherein the non-pathogenic non- viable Mycobacterium is selected from M. vaccae, M. obuense, M. paragordonae (strain 49061), M parafortuitum, M. paratuberculosis, M. brumae, M. aurum, M. indicus pranii, M. manresensis, M kvogaense (as deposited under DSM 107316/CECT 9546), M phlei, M smegmatis, M. tuberculosis Aoyama B or H37Rv, RUTI, BCG, VPM1002BC, SMP-105, or Z-100, wherein said non-pathogenic non-viable Mycobacterium is the rough variant and presented as a fraction, fragment, sub-cellular component, lysate, homogenate, sonicate, or in whole cell form, wherein 1 to 3 doses of the non-pathogenic non-viable Mycobacterium is administered prior to tumour resection surgery and/or administration of said one or more additional anticancer treatments or agents.
Claims 38 encompass several types and form of cancers, however the specification does not teach the treatment of all types and 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 uncertainty regarding the use of the method for the type and form of cancer mentioned above. Thus, one of ordinary skill in the art would not readily recognize the use of the method to treat all types and 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. Therefore, the written description requirement is not fulfilled by the applicant.
From the Court decision, AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) with regard to the written description requirement, “analogizing the genus to a plot of land, if the disclosed species only abide in a corner of the genus, one has not described the genus sufficiently to show that the inventor invented, or had possession of, the genus. He only described a portion of it.” Indeed, that is the case here too. The decision continues, explaining:
With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that “merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim’s functional boundaries.”). Id. p. 23.
In order to comply with the written description requirement, the applicant must fully disclosure all type and forms of cancers claimed to be treatable by the applicant’s invention regarding 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 any types and forms of cancer recited in claims 38 and dependent claims 39-41, 45, 48, 50-55.
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 each of the cancer types and 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 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.)
The specifications teaches that 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 all types and forms of cancer encompassed in claim 38 and dependent claims, especially 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. Further, 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. 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 38 encompass a group of types and 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 types and forms of the cancer in claim 38.
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.
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 provides a representative number of cancers that can be 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 ordinary skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
The claimed method further recites other non-pathogenic non-viable Mycobacterium selected from M. vaccae, M. obuense, M. paragordonae (strain 49061), M parafortuitum, M. paratuberculosis, M. brumae, M. aurum, M. indicus pranii, M. manresensis, M kvogaense (as deposited under DSM 107316/CECT 9546), M phlei, M smegmatis, M. tuberculosis Aoyama B or H37Rv, RUTI, BCG, VPM1002BC, SMP-105, or Z-100. 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 claims 41, 51-52. Claim 38 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 41, 51-52.
The specification teaches “the non-pathogenic non-viable Mycobacterium is the rough variant and is a presented as a fraction, fragment, sub-cellular component, lysate, homogenate, sonicate, or 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 the treatment to treat types and forms of cancers using each rough variants of non-pathogenic non-viable Mycobacterium and presented by fraction, fragment, sub-cellular component, lysate, homogenate, sonicate, or in whole cell form listed in the claim 38 used to treat the types and forms of cancer in the invention. Since a fraction or fragment of the rough variant, it could be any fraction, fragment and sub-cellular component. For example, a fraction of outer membrane proteins of a specific rough variant or any other proteins, nucleic acids, cell components and sub-cellular components.
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.
"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 in whole cell form from the Mycobacterium is actually used for the method in claim 38. In addition, there is minimal written description on how to obtain the subjects in the invention. 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 treating all types and forms of cancers claimed in the invention. 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 ordinary skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
New Claim Rejections - 35 USC § 103
Necessitated by Amendment
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 38-41, 45, 48, 50-55 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) and evidenced by Dalgleish et al. (Published August 14, 2018; hereafter Dalgleish; PTO-892).
Costa Neves teaches a patient with metastatic pancreatic cancer who underwent a synchronous resection of the primary tumour (pancreatoduodenectomy) and metastatic site (left hepatectomy) after multimodality neoadjuvant treatment with gemcitabine, nab-paclitaxel, and immunotherapy backbone with IMM-101 (an intradermally applied immunomodulator), as well as consolidation chemoradiation, which is pertinent to claims 38, 41, 51.
Costa Neves teaches “IMM-101 is a suspension of heat-killed whole cell Mycobacterium obuense (NCTC13365) administered by intradermal injection. It acts as a systemic immunomodulator, which has effects on innate and adaptive immune responses and may have application across a variety of tumor types”, which is pertinent to claim 38, 50.
Costa Neves teaches “nab-paclitaxel was added to the gemcitabine and IMM101 combination”, which is pertinent to claim 38, 51, 55.
Costa Neves teaches “The FOLFIRINOX regimen, whilst more toxic, also demonstrates a significant survival benefit in metastatic disease”, which is pertinent to claim 51.
Costa Neves teaches “The patient demonstrated an excellent and sustained partial response for the following six cycles, which is pertinent to claim 38.
Costa Neves teaches that following completion of radiotherapy, capecitabine and IMM-101 were continued as maintenance therapy, which is pertinent to claims 38, 41, 51”.
Costa Neves teaches that “four months after chemoradiotherapy, an FDG-PET scan showed no avidity in either the primary tumor or the liver”, which is pertinent to claim 38, 41.
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, which is pertinent to claim 38, 50.
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, which is pertinent to claim 38.
Costa Neves teaches “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. Patient 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”, which is pertinent to claim 38, 53.
Costa Neves teaches that “The efficacy of gemcitabine with or without nab-paclitaxel on an immunotherapy backbone of IMM101 reflects the promising results of the IMAGE-1 trial”, which is pertinent to claims 38, 51.
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”, which is pertinent to claim 38-40.
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”, which is pertinent to claim 38, 40.
Costa Neves teaches “A complete pathological regression of both primary pancreatic and metastatic disease, a very rare event”, which is pertinent to claim 38.
Costa Neves teaches that “initially, the patient demonstrated a partial response; however, she progressed after six cycles and nab-paclitaxel was added to the gemcitabine and IMM-101. After six months, she showed a sustained partial response on imaging and a marked tumour marker response. In view of the suggested alteration in tumour behavior, the patient received consolidation chemoradiation, continuing with IMM-101, and was operated on 18 months after starting treatment, in keeping with our neoadjuvant/downsizing pathway for locally advanced primary cancer. Most exceptionally, the specimens showed a complete response both in the primary and metastatic sites in the liver. This exceptional response to initial chemo-immunotherapy was followed by a novel and off-protocol approach of low-dose capecitabine and IMM-101 as a maintenance strategy. Remarkably, she has remained disease-free for twelve months and is still alive four years after her initial diagnosis. This survival benefit and sustained performance status could set this as a new paradigm for the treatment of oligometastatic pancreatic cancer following response to systemic therapy and immunotherapy, which is pertinent to claims 38, 51, 55.
Costa Neves that “the clinical behavior illustrates the characteristic tail to survival curves found in trial data of immunotherapy studies in cancer”, which is pertinent to claims 38-40, 50.
However, Costa Neves does not explicitly teach a dose comprising 103-109 cells, or 0.0001 to 1.0 mg as claim 48.
Costa Neves does not teach checkpoint inhibitors administered in a sub-therapeutic amount as claim 52.
Costa Neves does not teach checkpoint inhibitors are each administered in a sub-therapeutic amount as claim 53.
Costa Neves does not teach checkpoint inhibitors are each administered in a therapeutic amount for a shorter duration of time than when the one or more checkpoint inhibitors are administered alone for the treatment of cancer as claim 54.
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”, which is pertinent to claim 48. See for example paragraph [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”, which is pertinent to claim 52, 54. See for example paragraph [0031].
Biot teaches that “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”, which is pertinent to claims 52, 54. See paragraph [0032].
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, which is pertinent to claims 51, 53.
Dalgleish teaches “Enhanced effect of checkpoint inhibitors when given after or together with IMM-101: significant responses in four advanced melanoma patients with no additional major toxicity”, which is pertinent to claims 38-41, 45, 48, 50-55.
Dalgleish teaches that “The use of checkpoint inhibitors (ipilimumab, pembrolizumab, nivolumab) has revolutionized the treatment of metastatic melanoma. However still more than the half the patients do not respond to single-agent immunotherapy. This has led to the development of combining these agents in an attempt to enhance the anti-cancer activity. More than 300 different studies with 15 different drug doses are currently ongoing. Combining different checkpoint inhibitors (CPIs) does indeed lead to an increase in response rate, but this is associated with significant toxicity. IMM-101 is a heat killed Mycobacterium preparation which induces marked immune modulation and little systemic toxicity. It has been reported as having activity in melanoma as single agent and in pancreatic cancer in combination with gemcitabine, the latter in a randomised study”, which is pertinent to claims 38-47, 49, 50-51, 54-55.
Dalgleish teaches that “All 4 patients had rapid and very good responses, three of them maintained over 18 months with no significant additional toxicity”, which is pertinent to claims 38-41, 45, 48, 50-55.
Dalgleish teaches that “preclinical studies IMM-101 has shown to stimulate an immune response suppressed by the underlying tumour, which may enhance responses to other modalities of treatment. Altogether 11 patients with metastatic melanoma have been treated with IMM-101 and CPIs either sequentially or concomitantly. Despite the majority of these patients were previously pre-treated, about the half of them experienced some kind of benefit. Four of them had an exceptionally good and rapid response and have been presented here. The CR rate with ipilimumab in melanoma is less than 3%. We reported 2 cases that had both received prior IMM-101 treatment and experienced a very good response with ipilimumab; one CR which lasted for a couple of years until unexpected trauma and the other with no new disease for 5 years. Although the CR for PD-1 inhibitors is higher, complete responses may take months before they become manifest. Here we presented a case of widespread stage IV M1c disease that had, following prior IMM-101 treatment, an objective response observed 4 days after the first infusion with the anti-PD1 antibody pembrolizumab and another case of a rapid complete response to treatment when IMM-101 was given in combination with the anti-PD1 antibody nivolumab”, which is pertinent to claims 38-41, 45, 48, 50-55.
Dalgleish teaches that “Immune checkpoint blockades or checkpoint inhibitors (CPIs) have emerged as a major breakthrough for patients with metastatic melanoma and more recently they have been licensed in other tumour types. Ipilimumab is an anti-CTLA-4 antibody which showed to significantly improve long term survival of patients with metastatic melanoma being up to 20% of the treated patients alive at 5 years in spite of a low response rate (overall response rate [ORR] is around 10% with a complete response [CR] rate of less than 3%). Anti-PD1 antibodies (pembrolizumab and nivolumab) have shown higher response rates (ORR around 40%) and long duration of response with a more favourable toxicity profile in comparison to ipilimumab. The combination of nivolumab and ipilimumab has shown even higher response rates (58% ORR with 19% CR) similar to the ones seen with BRAF + MEK inhibitors, but this came at a price of greater toxicity (55% of the patients on the combination regiment experience a major toxicity which usually requires hospitalization and treatment discontinuation), which is pertinent to claims 39-41, 52-55.
Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings of Costa Neves and Biot, and evidenced by Dalgleish thereby arriving at the invention 38-47, 49 and 50-51. Since Costa Neves taught a successful method of treating aggressive type/form of pancreatic cancer (PDAC) in a patient by combining the use of standard anticancer therapies/treatments with non-pathogenic nonviable Mycobacterium strain (M. obuense as known as IMM-101) and Biot also teaches a method to treating cancer, combining anticancer therapies such as checkpoint inhibitors with non-pathogenic Mycobacterium strain, it would be very beneficial and desirable to treating cancer by combining non-pathogenic Mycobacterium and the checkpoint inhibitors because Mycobacterium has the effect of boost the immune system and it would make possible to administer lower doses of checkpoint inhibitors that are toxic if administered in combination and/or high-doses to a cancer patient as evidenced by and evidenced by Dalgleish, it would have been obvious to substitute these known equivalents; See MPEP 2144.06.
MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain predictable results is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results". In the instant case, Costa Neves teaches a method that only differs from the claimed invention by the substitution of a single element (i.e. regimes of doses/administration of anticancer therapies, types/form of cancer, Mycobacterium strain); the substituted element (lower doses and anticancer therapies/treatments/procedures; checkpoint inhibitors; M. obuense) was already known to be used to treat types and form of cancers, therefore no change in the function of the substituted element occurred; and one of ordinary skill in the art would be capable of substituting an antigen for another with a reasonable expectation of success (i.e. the substitution of the element would lead to predictable results).
Furthermore, In re Kerkhoven (205 USPQ 1069, CCPA 1980) summarizes:
"It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for the same purpose in order to form a combination that is to be used for the very same purpose: the idea of combining them flows logically from the individual teachings in the prior art."
Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Arguments directed to 103 rejections for claims 38-41, 45, 48, 50-55 will be addressed below. See response to arguments.
Response to Amendments
Applicant’s arguments as they pertain to the rejections have been fully considered but are not persuasive for the following reasons.
Applicant argues at pg. 10 of the Response (filed 6 July 2026) that “The as-filed application describes the claimed method of treating cancer that applies to the recited types of cancers such that one skilled in the art recognized that the Applicant was in possession of the method claimed”.
In response to Applicants arguments it is noted that the specification only teaches the potential application of non-pathogenic non-viable Mycobacterium for treating all types and forms of cancers in the invention based on the premise that the non-viable Mycobacterium stimulates the immune response, however there is no teachings in the specification indicating that the claimed method was/is practiced to every single form and type of cancer in the claims. Further, the Applicant’s assertions that “the capability of the non-pathogenic non-viable Mycobacterium to prime the cancer patient's innate immune system results in a therapeutic effect that is fully operative across the claimed tumour types and that “the method targets the tumour-agnostic, universal physiological phenomenon of trauma-induced systemic immunosuppression during surgical resection to elicit the innate immune mechanisms discussed above”. However, Applicant’s assertions are merely assumptions if there is a lack of evidences, show case based on support data for each type and form of cancer claimed in the invention. Furthermore, Applicant’s arguments acknowledge that the non-pathogenic bacteria “may” further boost anti-tumour responses (Specifications; page 8, lines 16-20) and activates other immune cells that “can” enhance anti-tumour responses and prevent the formation innate and type-1 immunity the formation of immune-suppressive M2 macrophages (Specifications; page 8, lines 20-24). See pages 10-11. Also, Applicant asserts that “the method targets the “tumour-agnostic”, universal physiological phenomenon of trauma-induced systemic immunosuppression during surgical resection to elicit the innate immune mechanisms discussed above”. Therefore, there is no show case in the specifications that the method claimed in the invention is capable of treating all types/forms of cancers. For all these reasons the specification lacks adequate written description, and one of ordinary skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Applicant is reminded that the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Moreover, Applicant is reminded that an adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for treating cancer.
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.
Applicant argues at pg. 10 of the Response (filed 6 July 2026) that 1) that “claim 38 has been amended to recite a method of treating Stage I, II, or III (non-metastatic) patients comprising administering 1 to 3 doses of the non-pathogenic, non-viable Mycobacterium prior to tumour resection surgery and/or administration of said one or more additional anticancer treatments or agents. Thus, Costa Neves does not disclose each and every element arranged as in the claims and does not anticipate the claims”. 2) Costa Neves reports a single exceptional case of metastatic (stage IV) PDAC treated with induction chemotherapy, chemoradiotherapy, and multiple intradermal injections of IMM-101 (heat-killed M. obuense) administered over an extended period before and after surgery. The authors emphasize that such long survival is rare in metastatic PDAC, and they neither disclose a defined short pre-resection priming window nor demonstrate that a low number of doses of any heat-killed mycobacterium, administered shortly before surgery, is sufficient to prime durable anti- tumour T-cell responses. Costa Neves therefore does not teach the specific low-dose, pre-resection non-pathogenic non-viable Mycobacterium-based priming strategy claimed”.
In response to applicant’s arguments that Costa Neves does not disclose each and every element arranged as in the claims and does not anticipate the claims, the examiner has reexamined the claims and reintroduced the rejections under 103 in view of Applicant’s amendments to claims. For the sake of clarity, the examiner will point out the obviousness of the inventions in claims 38-47, 49, 50-51, 54-55.
Applicant should recognize that Costa Neves teaches a successful method of treating pancreatic cancer (PDAC) in a human patient. The method taught by Costa Neves comprises the administration of heat-killed Mycobacterium obuense (also known as IMM-100 or “rough variant” as in specifications), administration of anticancer therapies, and standard procedures that are applicable depending on the type/form of cancer. Costa Neves explicitly teaches the benefits of using a nonviable (heat-killed) nonpathogenic Mycobacterium. Costa Neves’ rationale/motivation for administering non-pathogenic Mycobacterium to a cancer patient is supported by the systemic immunomodulator activity of nonpathogenic Mycobacterium, which has effects on innate and adaptive immune responses and may have application across a variety of tumor types. It is apparent that Applicant acknowledges that “administering the claimed non-pathogenic non-viable mycobacterium to patients having one of the recited cancers optimally primes the patient's innate immune system. The capability of the non-pathogenic non-viable mycobacterium to prime the cancer patient's innate immune system results in a therapeutic effect that is fully operative across the claimed tumour types”. See applicant’s arguments at page 10; See specifications; page 8, lines 16-20. Thus, the stimulation of the immune system by non-pathogenic Mycobacterium is the motivation and consequently a common structural element between the prior art and the present application. Further, Costa Neves teaches a patient with pancreatic cancer, a PADC. The applicant should recognize that Costa Neves teaches essentially a method comprising nonpathogenic Mycobacterium and well-known anticancer therapies and procedures tailored for what is known for a patient with PADC, considering patient’s overall health conditions and age. Thus, it would be obvious to adapted the protocol by adjusting all the doses, and procedures, because it is reasonable and expected to encounter response variations to the treatments in cancer patients.
It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Furthermore, in response to applicant's argument that the examiner's conclusion of obviousness is based upon “most fairly be described as teachings” reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon straightforward evidences. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues at pg. 13-14 of the Response (filed 6 July 2026) that “one skilled in the art would not have been motivated to combine Costa Neves and Biot, two references that are directed to different immunomodulator treatments (heat-killed whole cell mycobacteria in Costa Neves versus live or metabolically active mycobacteria in Biot), using different treatment schemes of mycobacterial administration. Further, Biot teaches that priming before tumour resection must be performed with live or metabolically active mycobacteria, not fully heat-killed material. Biot teaches that the priming parenteral/oral first composition given "before tumor resection" is limited to "live or killed but metabolically active non-pathogenic mycobacteria". Biot directs the skilled person to use live or metabolically active mycobacteria for pre-resection priming and live, high-dose BCG for local therapy.
In response to Applicant’s arguments, the examiner reminds the applicant that the common structural elements claimed in the invention, which are the novel therapeutic agent used to boost immune response Mycobacterium, cancer and well-known anticancer therapies/procedures/treatments are the basis for the 103 rejections. Costa Neves and Biot teach a method comprising Mycobacterium, anticancer drugs, anticancer therapies and surgery for treating cancer patients. Additionally, Biot does teach the use of whole cell, live or killed, non-pathogenic mycobacteria, and nonpathogenic mycobacteria include naturally avirulent Mycobacterium species, attenuated strains (genetically modified or not) of Mycobacterium sp., and recombinant strains derived from the preceding strains. See Biot et al. paragraph [0017]. Biot teaches the use of Mycobacterium for boosting the specific immune response. See Biot et al. paragraph [0028]. Biot teaches the use of anticancer drugs, including checkpoint inhibitors, which are blocking antibodies directed against T-cell negative co-stimulatory molecules (CTLA-4, PD-1, TIM-3, BTLA, VISTA, LAG-3). Even tough, Biot taught treating bladder cancer and better results achieved by using live BCG bacteria, it does not eliminate the obviousness because the novelty is the use of a bacteria, such as Mycobacterium for treating cancer in combination with well-known methods to treat cancers to boost the immune system response. The applicant should recognize that both methods taught by prior arts share the same combined structural elements claimed in the present invention, which is Mycobacterium aiming the boost of immune response, and a combination of chemotherapies, anticancer therapies, and procedures such as surgeries to treat a patient with cancer.
Applicant argues at pg. 14 of the Response (filed 6 July 2026) that “neither Costa Neves nor Biot teach or suggest administration of a sub-therapeutic amount of a checkpoint inhibitor or the administration of a therapeutic amount of one or more checkpoint inhibitors for a shorter duration of time as compared to when the one or more checkpoint inhibitors are administered alone for the treatment of cancer. Furthermore, the combined references fail to teach or suggest a method as claimed where the recited non-pathogenic non-viable mycobacterium is a rough variant and is administered for 1 to 3 doses prior to tumour resection and/or administration of one or more additional anticancer treatments. In fact, from the teachings of the combined cited references as discussed, one skilled in the art would not have had a reasonable expectation of successfully arriving at a method of treating cancer as claimed, where a rough variant non-viable non- pathogenic mycobacterium is administered for 1 to 3 doses to a cancer patient”.
In response to Applicant’s arguments, the examiner recognizes that the prior art does not explicitly teaches the sub-therapeutic doses of checkpoint inhibitors. However, it would be obvious to one skilled in the art to adjust the doses/duration of checkpoint inhibitors because as evidenced by Dalgleish, there is enhanced effect of checkpoint inhibitors when given after or together with IMM-101, and the significant responses in cancer patients with no additional major toxicity, which supports the lower doses/duration of regimen of doses. Thus, the immune stimulatory effect of Mycobaterium is the rationale/motivation for adding Mycobacterium to a protocol of checkpoint inhibitors to treating cancer.
It would be desirable and very beneficial to decrease doses and/or administration duration of checkpoint inhibitors. The checkpoint inhibitors are first line choice therapy for cancer treatments, because of it also stimulates the immune system, however they can be toxic if the use is prolonged and in higher doses.
Therefore, it would have been prima facia obvious to a person of ordinary skill in the art at the time the invention was filed to combine Mycobacterium to a cancer treatment protocol/method as way to maintain optimal levels of immune system stimulation combined with sub-therapeutic doses of checkpoint inhibitor(s). This combination would be very desirable and beneficial because it would be an advantage to use Mycobacterium to boost the immune system response as a way to balance the lower doses (sub-therapeutical) of checkpoint inhibitors. Since the administration of checkpoint inhibitors to patients usually cause toxic effects, the combination of these anticancer antibodies with Mycobacterium would make possible to decrease or eliminate the toxic effects caused by the administration of checkpoint inhibitors to a cancer patient without compromising the levels of overall immune response needed to fight cancer.
One of ordinary skill in the art at the effective filling date would have had a reasonable expectation of success in practicing the invention as claimed, since such drugs were commercially available and commonly used for cancer therapy, including checkpoint inhibitors and the combination of nonpathogenic Mycobacterium strains such as M. obuense (IMM-101) with anticancer therapies have already been used for treating patients with cancer as taught by prior arts mentioned above.
Motivation for combining the references is clear from the teachings as each reference teaches the structural elements of the claimed method. While there is not a single reference that includes all the limitations of the claims, the various aspects of the claims are contained in multiple references and it would have been prima facie obvious to combine the teachings as stated above to arrive at the claimed invention with an expectation of success for the reasons provided, it would have been obvious to substitute these known equivalents; see MPEP 2144.06.
KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain predictable results is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results".
***
Response to Amendments
Applicant does not offer further arguments regarding the above obviousness rejections beyond what was set forth with regard to the 35 U.S.C 103 rejection above. To extend the Applicant is merely repeating their previous argument, the Examiner contends that those issues were adequately addressed in above sections, which are incorporated in their entireties herein by reference.
Conclusion
No claim is allowed.
Applicant’s amendment necessitated the new ground(s) of rejection presented in the Office action. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Advisory Information
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/PRICILA NMN HAUK TEODORO/Examiner, Art Unit 1645
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
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