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 .
The response filed 2-18-2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of A- ionizing radiation, B- surgical tumor resection therapy and C- pancreatic cancer in the reply filed on 2-182-2026 is acknowledged.
Claims 106-108 are withdrawn from consideration as drawn to non-elected species.
Claims 100-105 and 109-118 are under examination.
Information Disclosure Statement
The information disclosure statement has been considered. An initialed copy is enclosed.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Applicant’s attention is drawn to at least page 83, Example 2. Applicant should review the rest of the specification to ensure correction of any other recitation of embedded hyperlinks or browser-executable code.
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 100-105 and 109-118 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 enablement requirement. The claim(s) 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.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: 1) scope or breadth of the claims; 2) nature of the invention; 3) relative level of skill possessed by one of ordinary skill in the art; 4) state of, or the amount of knowledge in, the prior art; 5) level or degree of predictability, or a lack thereof, in the art; 6) amount of guidance or direction provided by the inventor; 7) presence or absence of working examples; and 8) quantity of experimentation required to make and use the claimed invention based upon the content of the supporting disclosure. When the above factors are weighed, it is the Examiner’s position that one skilled in the art could not practice the invention without undue experimentation.
While all of the factors have been considered, only those deemed necessary to establish a prima facie case are set forth below.
Scope or breadth of the claims
The claims are drawn to a method of treating or controlling cancer comprising a primary tumor in a patient comprising simultaneously, separately, or sequentially administering to the subject 1- one or more doses of ionizing radiation and 2- a non-pathogenic non-viable Mycobacterium where in the method results in enhanced therapeutic efficacy relative to either 1- or 2- alone. The cancer can be any cancer, and particularly include diverse cancers such as: 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, leukemia, 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 (PNET), optionally wherein said cancer is metastatic. In addition, one or more additional anticancer treatments can be administered such as: additional anticancer treatments or agents is selected from adoptive cell therapy, surgical tumor resection therapy, chemotherapy, 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. The elected invention is pancreatic cancer. The Mycobacterium can be any Mycobacterium spp and radiotherapy can be of any type/duration.
Knowledge of the prior art
At the time of invention, pancreatic cancer is found to be the fourth leading cause of cancer-related death, fewer than 20% of patients with tumors amenable to resection and the 5-year overall survival rate of less than 25%. The role of radiation therapy in the treatment of pancreatic cancer at the time was uncertain. The benefits of radiation therapy were controversial with different studies showing either no benefit or an OS and disease-free survival benefit (see Palta et al (Practical Radiation Oncology 9:322-332, 2019; page 325, column 1, first and second paragraphs). The treatment and management of pancreatic cancer is complex and depends upon multiple factors such as the ability to initially present with resectable disease for surgery. The combination of neoadjuvant therapy and adjuvant therapy depends upon upfront resectable, locally advanced pancreatic cancer (inoperable) and borderline resectable cancer. Neoadjuvant and adjuvant approaches include chemotherapy, chemosensibilization concominant to long course conventionally fractionated radiotherapy and stereotactic body radiotherapy. (see Cellini et al Cancers, 12:1729, pages 1-40, 2020; page 2, section 1 and 1.1). Definitive evidence on the most effective treatment option for each presentation is still lacking due to weak and sometimes contradictory results (see Cellini et al at page 3, section 1.5). Cellini et al teach that the integration of radiotherapy with immunotherapy is one of the most promising modern opportunities and clinical integration will be determinant in their efficacy (see page 30, first paragraph). There is no evidence that the method comprising administration of a non-pathogenic non-viable Mycobacterium, administration radiotherapy of any type and optionally one or more additional anticancer treatments or agents, or tumor resection surgery provides for enhanced therapeutic efficacy in pancreatic cancer patients as claimed or in a representative number of cancers set forth in the specification as filed or in instant claim 118. The specification does not teach therapeutic efficacy for each of the claimed therapeutic modalities in different cancer patients and the specific therapeutic efficacy point that is enhanced. This is particularly important as comparing therapeutic efficacy of pancreatic cancer patients with different disease categorization can be substantially different. As such, outcomes cannot be compared against a known standard and the ability to determine “enhanced” for a combination when the individual results are not set forth in the specification as filed.
Additionally, as compared to the use of the genus of “Mycobacterium” set forth in the claims, 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. The courts have held that the disclosure is insufficient when testing is necessary to determine the actual use or possible lack of use (In re Kirk and Petrow 153 USPQ 48 (CCPA 1967). As such, the genus of non-viable, non-pathogenic Mycobacterium for the treatment of cancer and pancreatic cancer in particular is not enabled.
As such, “therapeutic efficacy” for each of the radiotherapy modalities and for non-viable non-pathogenic Mycobacterial treatment for cancer in general and pancreatic cancer is highly unpredictable and the definition of enhanced clearly depends upon what parameter is being measured and none are set forth for pancreatic cancer.
Guidance provided by inventor/working examples
The specification provides for prophetic examples of studies that will be performed. No results from any cancer tumor treatment as set forth in claims 100 or 118 meeting the limitations set forth therein are presented. No combination is provided that provide for enhanced therapeutic efficacy for any cancer is shown. The specification provides for a list of potential combinations that may or may not provide for enhanced therapeutic efficacy as claimed. NO in vitro or animal model studies have been presented that reasonably correlate with in vivo studies in humans as set forth in the specification. The “therapeutic” endpoints are not disclosed for the individual therapies. No combination has been presented with “enhanced” therapeutic efficacy has been presented. See Rasmussen v. SmithKline Beecham Corp., 413 F.3d 1318, 1325 (Fed. Cir. 2005) “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to ‘inventions' consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the ‘inventor' would be rewarded the spoils instead of the party who demonstrated that the method actually worked.” “A patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” (Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997)).
Level or degree of predictability
The treatment of pancreatic cancer is complicated, dependent on multiple different factors. There is no consensus as to what provides for therapeutic efficacy and no consensus on specific treatment plans. There is a high degree of picking and choosing among known radiation and chemotherapeutic therapies to see, what if anything can treat or delay disease progression among pancreatic cancer patients. In addition, the use of Mycobacteria in the treatment of cancer in general is unpredictable as set forth supra.
Quantity of experimentation
The quantity of experimentation is immense, and the skilled artisan would be randomly selecting radiotherapies with random non-pathogenic Mycobacteria with random cancer or cancer models, the individual therapeutic efficacies are not disclosed and the combination with particular cancers showing enhancement are not set forth. As such, the skilled artisan has to randomly select a cancer, define therapeutic efficacy for each treatment alone and then test to combine to see if the combination provides for enhanced efficacy without any reasonable expectation of success. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
In light of the foregoing factors, the evidence as a whole suggests that the specification, in light of the level of knowledge in the art, does not enable one of ordinary skill to make or use the invention over the full scope of the instant claims without undue experimentation and in particular as it relates to the elected pancreatic cancer. Consequently, the claims are prima facie non-enabled.
Double Patenting
The USPTO may not institute a derivation proceeding in the absence of a timely filed petition. The U.S. Patent and Trademark Office normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). The applicant should amend or cancel claims such that the applications no longer contain claims directed to the same invention.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 100, 101, 104, 105, 109, 110, 113, 114, 115 and 118 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,318,193. Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims anticipate the instant claims.
Although the patent is silent about the enhanced therapeutic efficacy, it does not appear that the claim language or limitations result in a manipulative difference in the method steps when compared to the prior art disclosure. See Bristol-Myers Squibb Company v. Ben Venue Laboratories 58 USPQ2d 1508 (CAFC 2001). {i}t is a general rule that merely discovering and claiming a new benefit of an old process cannot render the process again patentable. In re Woodruff, 16 USPQ2d 1934, 1936 (Fed. Cir. 1990). The mechanism of action does not have a bearing on the patentability of the invention if the invention was already known or obvious. Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 201 USPQ 658 (CCPA 1979). Granting a patent on the discovery of an unknown but inherent function would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art. In re Baxter Travenol Labs, 21 USPQ2d 1281 (Fed. Cir. 1991). See M.P.E.P. 2145.
Claims 100-102, 104, 105, 109, 110, 113, 115, 117 and 118 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 5 and 9 of U.S. Patent No. 11,554,166. Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims anticipate the instant claims.
Although the patent is silent about the enhanced therapeutic efficacy, it does not appear that the claim language or limitations result in a manipulative difference in the method steps when compared to the prior art disclosure. See Bristol-Myers Squibb Company v. Ben Venue Laboratories 58 USPQ2d 1508 (CAFC 2001); set forth supra.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 100-102, 104-105, 109-111, 113, 114, 115, 117, and 118 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Costa Neves et al (Cureus 7(12):e435 pages 1-8, published 12-26-2015).
Costa Neves et al teach the treatment of a patient having pancreatic ductal adenocarcinoma with metastatic disease. The prognosis was poor and a median survival for metastatic patients is 6-9 months and survivors beyond one year are exceptional. Costa Neves et al teach that the patent presented with initially inoperative cancer. Restaging prior to commencement of palliative chemotherapy showed two new masses in the left liver not evident on the preoperative stages and were confirmed as metastases. The patient received three cycles of gemcitabine and IMM-101 (Mycobacterium obuense (NCTC 13365) by intradermal injection. A CT scan showed partial remission at the primary and metastatic sites. After one month nab-paclitaxel was added to the gemcitabine and IMM-101. The patient demonstrated excellent and sustained partial response following six cycles. The liver shoe a complete radiological response. The patient was given consolidation chemoradiation two weeks after her last cycle, to a dose of 59.4 Gy in 33 fractions with concomitant capecitabine and IMM-101. Following completion of radiotherapy, capecitabine and IMM-101 were continued as maintenance therapy (see page 3 paragraphs 1-3, Figure 3, page 5. Six weeks after completion of chemoradiation, the patient underwent surgery pylorus-preserving pancreatodudoenectomy including a left hepatectomy, coeliac and retroperitoneal nodal dissection. Post operatively the patient continued to receive IMM-101 and restarted capecitabine 10 weeks after the operation. At twelve months after surgery a CT scan showed bilateral small volume lung metastases and further solitary lesion in the liver. The patient received radiofrequency ablation to both lungs, CyberKnife stereotactic radiation to the liver and restarted gemcitabine + nab-paclitaxel. The patient maintains a good quality of life for 4 years after diagnosis of metastatic pancreatic ductal adenocarcinoma (see pages 4-5). While the data does not state that the therapy is enhanced compared to either alone, the functional property is necessarily present as the patient was administered the same treatments.
Claims 100, 101, 104, 105, 109, 110, 113, 114, 115 and 118 is rejected under 35 U.S.C. 102(a)(2) as being clearly anticipated by Akle et al (US 11,318,193, with priority to December 3, 2012) or Akle et al (US 11,554,166, with priority to December 3, 2012). The teachings of the Akle references are identical.
Akle et al teach radiation therapy for ablation combined with the administration of an immunomodulator where the immunomodulator is a non-viable non-pathogenic Mycobacterium (see column 8, line 9 – column 9, line 23; column 5, second full paragraph) for the treatment, control or inhibition of a neoplastic disease, where the neoplastic disease is preferably pancreatic cancer (column 7, line 35). The Mycobacterium can be administered before and/or after the disruption of the tumor and the immunomodulator may be administered in repeat doses (see column 8, lines 10-17). The immunomodulator may be administered by intradermal, subdermal or a variety of other routes (column 8, lines 33-40). In a preferred embodiment the cell death is ionizing radiation such as gamma rays, UV-C irradiation, targeted radiation and the like and combined with the immunomodulator. The dose of the radiation can be fractionated (see column 9, lines 7-17). Tumor disruption therapy can happen simultaneously, separately or sequentially with administration of the immunomodulator. As such, Akle et al anticipate the claimed invention.
Although the patent is silent about the enhanced therapeutic efficacy, it does not appear that the claim language or limitations result in a manipulative difference in the method steps when compared to the prior art disclosure. See Bristol-Myers Squibb Company v. Ben Venue Laboratories 58 USPQ2d 1508 (CAFC 2001). {i}t is a general rule that merely discovering and claiming a new benefit of an old process cannot render the process again patentable. In re Woodruff, 16 USPQ2d 1934, 1936 (Fed. Cir. 1990). The mechanism of action does not have a bearing on the patentability of the invention if the invention was already known or obvious. Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 201 USPQ 658 (CCPA 1979). Granting a patent on the discovery of an unknown but inherent function would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art. In re Baxter Travenol Labs, 21 USPQ2d 1281 (Fed. Cir. 1991). See M.P.E.P. 2145.
Conclusion
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/Patricia Duffy/Primary Examiner, Art Unit 1645
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