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
Election/Restrictions
Applicant’s election without traverse of Group I, colorectal cancer, Salmonella typhimurium, immune checkpoint inhibitors that target PD-L1 and the genetic modifications reIA, Spot, SPI1 and SPI2 in the reply filed on 6-23-2026 is acknowledged. Claims 23-39 and 43-44 are pending. Claims 31-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 23-30 and 43-44 are currently under examination.
Information Disclosure Statement
The Information Disclosure Statements filed on 5-3-2024 and 6-23-2023 have been considered. Initialed copies are attached hereto.
It should be noted that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 23-30 and 43-44 are objected to for reciting claim language drawn to non-elected inventions.
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 23-30 and 43-44 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(s) 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 methods of treating cancer utilizing a Salmonella strain (Salmonella typhimurium) and an immune checkpoint inhibitor (targeting PD-L1). The claims optionally require:
the Salmonella strain and the immune checkpoint inhibitor are co-administered (claim 24);
the Salmonella strain is Salmonella typhimurium, Salmonella choleraesuis, Salmonella enteritidis, Salmonella dublin, Salmonella. typhisuis, Salmonella derby, and Salmonella gallinarum (claim 25);
the Salmonella strain is Salmonella typhimurium (claim 26);
the immune checkpoint inhibitor targets comprises at least one selected from form the group consisting of cytotoxic T- lymphocyte-associated antigen-4 (CTLA-4), programed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), KIR, LAG3, CD137, OX40, CD47, CD276, CD27, and GITR (claim 27);
the immune checkpoint inhibitor targets programmed death-ligand 1 (PD-L1) (claim 28);
the cancer comprises at least one selected from the group consisting of melanoma, fallopian tube cancer, brain cancer, small intestine cancer, esophagus cancer, lymph node cancer, gallbladder cancer, blood cancer, thyroid cancer, endocrine cancer, oral cancer, liver cancer, biliary tract cancer, colorectal cancer, rectal cancer, cervical cancer, ovarian cancer, kidney cancer, gastric cancer, duodenum cancer, prostate cancer, breast cancer, brain tumor, lung cancer, undifferentiated thyroid cancer, uterine cancer, colon cancer, bladder cancer, ureteral cancer, pancreatic cancer, bone/soft tissue sarcoma, skin cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and solitary myeloma (claim 29);
the composition inhibits cancer growth or cancer metastasis (claim 30);
the Salmonella strain is deficient in the reIA and spoT genes; and
the Salmonella strain is deficient in the reIA, spoT, SPIl and SPI2 genes.
Consequently, the instant claims are drawn to methods of treating any and all cancers utilizing any and all Salmonella stains in combination with any and all immune checkpoint inhibitors.
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. To adequately describe the genus of cancer therapeutics comprising a Salmonella species and an immune checkpoint inhibitor with the claimed immunological and phenotypic characteristics, Applicant must adequately describe the specific Salmonella species (and genotype/phenotype thereof) that has efficacy in treating a given type of cancer when coupled with a given immune checkpoint inhibitor as well as any mutations, culture conditions, dosages and means of administration.
However, the specification does not disclose distinguishing and identifying features of a representative number of members of the genus of strains of Salmonella to which the claims are drawn, such as a correlation between the structure of the bacteria (i.e. genome and phenotype) and its recited function (i.e. treat of any and all cancers when coupled with a given immune checkpoint inhibitor) so that the skilled artisan could immediately envision, or recognize at least a substantial number of members of the claimed genus of cancer therapeutics. Applicant describes the use of the aforementioned Salmonella species (in conjunction with immune checkpoint inhibitors) to treat various cancers in a generalized and prophetic sense but fails to demonstrate the therapeutic efficacy of any microorganism with the claimed autotrophs comprising any of the claimed combinations of heterologous genes in any animal system. The specification is limited to the use of the CNC018 Salmonella strain in conjunction with an anti-PDL-1 antibody to treat CT26 and MC38 xenografts in mice. However, the specification does not provide any basis for correlating the in vitro and xenograft results with beneficial effects that could reasonably be expected when said recombinant microorganisms are administered in vivo to "treat" established melanomas or lymphomas, although in vivo use is clearly encompassed by the claims. Lacking either direct evidence for in vivo benefit, or a reasonable basis for correlating the in vitro and xenograft data (as exemplified in the instant specification) with in vivo benefit, the specification cannot be said to disclose how to use the claimed recombinant microorganisms and immune checkpoint inhibitors as pharmaceuticals (i.e. cancer therapeutics) without undue trial and error. Moreover, while those of skill in the art recognize that in vitro assays and or cell-cultured based assays are somewhat useful to observe basic physiological and cellular phenomenon such as screening the effects of potential drugs, clinical correlations are generally lacking. The greatly increased complexity of the in vivo environment as compared to the very narrowly defined and controlled conditions of an in vitro assay does not permit a single extrapolation of in vitro assays to in vivo efficacy with any reasonable degree of predictability. In vitro assays cannot easily assess cell-cell interactions that may be important in a particular pathological state. Furthermore it is well known in the art that cultured cells, over a period time, lose phenotypic characteristics associated with their normal counterpart cell type. Freshney (Culture of Animal Cells, A Manual of Basic Technique, Alan R. Liss, Inc., 1983, New York) teach that it is recognized in the art that there are many differences between cultured cells and their counterparts in vivo. These differences stem from the dissociation of cells from a three-dimensional geometry and their propagation on a two-dimensional substrate. Specific cell interactions characteristic of histology of the tissue are lost. The culture environment lacks the input of the nervous and endocrine systems involved in homeostatic regulation in vivo. Without this control, cellular metabolism may be more constant in vitro but may not be truly representative of the tissue from which the cells were derived. This has often led to tissue culture being regarded in a rather skeptical light (p. 4, see Major Differences In Vitro). Moreover, Dermer (Bio/Technology, 1994, Vol. 12, page 320) teaches that, "petri dish cancer" is a poor representation of malignancy, with characteristics profoundly different from the human disease Further, Dermer teaches that when a normal or malignant body cell adapts to immortal life in culture, it takes an evolutionary type step that enables the new line to thrive in its artificial environment. This step transforms a cell from one that is stable and differentiated to one that is not. Yet normal or malignant cells in vivo are not like that. The reference states that evidence of the contradictions between life on the bottom of a lab dish and in the body has been in the scientific literature 'for more than 30 years. Clearly it is well known in the art that cells in culture exhibit characteristics different from those in vivo and cannot duplicate the complex conditions of the in vivo environment involved in host-tumor and cell-cell interactions.
Moreover, on the basis of experimentation performed using an animal model, the specification asserts the invention can be used to treat a cancer. The problem with accepting such an assertion lies in the fact that the data generated using such models cannot be reasonably extrapolated to reliably and accurately predict whether the claimed invention can be used to attenuate at least a substantial number of pathoangiogenic conditions comprising cancer and furthermore, as of yet, the clinical, therapeutic application of cancer “vaccines” to attenuate cancer has been met with very little success. Wang et al. (Exp. Opin. Biol. Ther. 2001; 1 (2): 277-290) reviews the state of the art of T-cell-directed cancer vaccines for treatment of melanoma and states:
Saved for scattered reports, however, the success of these approaches has been limited and T-cell-directed vaccination against cancer remains at a paradoxical standstill whereby anticancer immunization can be induced but is not sufficient, in most cases, to induce tumour regression (abstract).
Wang et al. further states:
Among the questions raised by this paradoxical observation [that systemic T-cell responses to vaccines often do not lead to objective clinical tumor regression] stands the enigma of whether tumour resistance to immunotherapy is due to insufficient immune response or because tumour cells rapidly adapt to immune pressure by switching into less immunogenic phenotypes [citations omitted].
In addition, Kelland (Eur. J. Cancer. 2004 Apr; 40 (6): 827-836) has reviewed the reliability of the model in predicting clinical response; see entire document (e.g., the abstract). While the successful use of such models in cytotoxic drug development is conclusive, Kelland discloses that today there is far less focus on the development of such drugs (page 833, column 2); rather, the focus is upon the development of “molecularly-targeted”, largely cytostatic drugs, such as those disclosed in the instant application, which may act in synergy with other drugs to selectively reduce or inhibit the growth of neoplastic cells (e.g., page 885). In particular, where such drugs are naked humanized antibodies that act through mechanisms such as ADCC, Kelland states the models are of limited value, because such mechanisms depend upon the recruitment of the host’s (i.e., mouse) immune response, which differs from or is not reflective of that found in man (page 834, column 2). With such limitations of the xenograft model in mind, Kelland suggests that the case for using the model within a target-driven drug development cascade need to be justified on a case-by-case basis (page 835, column 1). Still, Kelland et al. does not altogether discount the usefulness of such models, since, at present, “it is premature and too much a ‘leap of faith’ to jump directly from in vitro activity testing (or even in silico methods) to Phase I clinical trials (via preclinical regulatory toxicology)” (page 835, column 2). Kelland, however, does not advocate the use of a single xenograft model to exhort one to accept assertions of the effectiveness of treating multiple and different diseases using the same agent, as has been done in the instant application, since Kelland compels one to decide on a case-by-case basis whether such a model is suitable or not.
Moreover, Gura (Science Vol 278, pages 1041-1042) teaches that although researchers had hoped that xenografts would prove to better models for studying cancer in humans and screening candidate therapeutic agents for use in treating patient diagnosed with cancer, “the results of xenograft screening turned out to be not much better than those obtained with the original models”. Gura states that as a result of their efforts, “ ‘[w]e had basically discovered compounds that were good mouse drugs rather than good human drugs’ ”.
With further regard to the predictive value of various different preclinical models, Voskoglou-Nomikos et al. (Clin. Cancer Res. 2003 Sep 15; 9: 4227-4239) reports in a retrospective analysis that mouse allograft models were not predictive and xenograft models were only predictive for non-small cell lung and ovarian cancers, but not for breast or colon cancers; see entire document (e.g., the abstract).
Finally, Saijo et al. (Cancer Sci. 2004 Oct; 95 (10): 772-776) recently reviewed the reasons for negative phase III trial of molecular-target-based drugs and their combinations; see entire document (e.g., the abstract). Saijo et al. discloses that while numerous phase III trials have been conducted upon the basis of promising preclinical data such as that disclosed in the instant application, few have yielded strongly positive results, and the majority of results have been negative (e.g., abstract). Saijo et al. discloses that there are problems in preclinical prediction of combined effects of anticancer drugs, and the results of preclinical prediction of combined effects have been very poor (page 773, column 2). Saijo et al. teaches many reasons for the poor predictability of combined effects (page 774, Table 6).
While the use of xenografts in mice for evaluating therapeutic efficacy of drugs for treating humans is well established, their use should not be considered sufficient to show that the efficacy of the claimed invention because of the poor extrapolation of the results to accurately and reliably predict the effectiveness of treating humans with the same agent or regimen. Schuh (Toxicologic Pathology. 2004; 32 (Suppl. 1): 53-66) reviews the trials, tribulations and trends in tumor modeling in mice to disclose, for example, that “[c]ommon reliance on survival and tumor burden data in a single mouse model often skews expectations towards high remission and cure results; a finding seldom duplicated in clinical trials” (abstract). Furthermore, Schuh discloses, “[d]espite historical significance and ongoing utility, tumor models in mice used for preclinical therapeutic intervention often error towards false positive results and curing cancer in mice” (page 62, column 1). Given the noted limitations of xenograft models, Schuh suggests that testing in tumor-bearing animals may help to improve the predictive value of animal modeling; see entire document (e.g., the abstract).
Bibby (Eur. J. Cancer. 2004 Apr; 40 (6): 852-857) teaches that in the interest of finding more clinically relevant models, orthotropic models have been developed; see entire document (e.g., the abstract). In such “orthotopic” models, treatment is initiated after removal of the primary tumor and distant metastases are well established and macroscopic. These models have their advantages, but the procedures involved in using such models are far more difficult and time-consuming than conventional subcutaneous (e.g., xenograft) models; see, e.g., page 855, column 2.
This position is further substantiated by the teachings of Peterson et al. (Eur. J. Cancer. 2004; 40: 837-844). Peterson et al. teaches numerous agents have shown exciting activity in preclinical models and yet have had minimal activity clinically; see, e.g., the abstract. Such disappointments, Peterson et al. discloses, “have led to reasonable skeptism about the true value of both syngeneic and xenograft rodent tumour models in accurately identifying agents that will have important clinical utility” (abstract). Peterson et al. reviews the limitations of the xenograft models; see entire document (e.g., page 840, column 2).
The specification does not provide substantive evidence that the claimed compositions are capable of inducing a directed therapeutic immune response against a given cancer. This demonstration is required for the skilled artisan to be able to use the claimed compositions for their intended purpose of treating a given cancer. Without this demonstration, the skilled artisan would not be able to reasonably predict the outcome of the administration of the claimed therapeutics, i.e. would not be able to accurately predict if therapeutic has been induced as the ability to reasonably predict the capacity of a single recombinant bacterial to induce a given therapeutic effect from in vitro or xenograft studies is problematic. The art, unfortunately, is replete with instances where even well characterized therapeutics that induce an in vitro or xenograft efficacy in treating a given cancer fail to elicit a directed (therapeutic) immune response in vivo.
Given the lack of success in the art, the lack of working examples and the unpredictability of the generation of a directed immune response, none of the claimed “cancer therapeutics” meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The specification provides insufficient written description to support the genus encompassed by the claims. Moreover, the specification fails to disclose what genotype/phenotype must be possessed by a given Salmonella strain to have efficacy treating a given cancer or the specific immune checkpoint inhibitor that must be used.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons 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. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
MPEP 2163.02 further states, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention” See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). Moreover, because the claims encompass a genus of variant species, 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 Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Additionally, MPEP 2163 states:
"A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)”
And:
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
Moreover, the describing of a biological entity by their functions was addressed in the Centocor decision (CENTOCOR ORTHO BIOTECH, INC. v ABBOTT LABORATORIES (Fed Cir, 2010-1144, 2/23/2011)). In said case the court stated”
To satisfy the written description requirement, "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,' and demonstrate that by disclosure in the specification of the patent." Carnegie Mellon Univ. v. Hoffmann-La Roche Inc., 541 F.3d 1115, 1122 (Fed. Cir. 2008) (quoting Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir. 1991)). Assessing such "possession as shown in the disclosure" requires "an objective inquiry into the four corners of the specification." Ariad, 598 F.3d at 1351. Ultimately, "the specification must describe an invention understandable to [a person of ordinary skill in the art] and show that the inventor actually invented the invention claimed." Id. A "mere wish or plan" for obtaining the claimed invention is not adequate written description. Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir. 1997).
The court further opined that Centocor's suggestion
that our decision in Noelle and the PTO written description guidelines support the view that fully disclosing the human TNF-α protein provides adequate written description for any antibody that binds to human TNF-α. That suggestion is based on an unduly broad characterization of the guidelines and our precedent.
The court concluded that
While our precedent suggests that written description for certain antibody claims can be satisfied by disclosing a well-characterized antigen, that reasoning applies to disclosure of newly characterized antigens where creation of the claimed antibodies is routine. Claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described.
Therefore, because the art is unpredictable, in accordance with the MPEP and currently caselaw, the description of claimed Salmonella species and immune checkpoint inhibitors is not deemed representative of the genus of cancer therapeutics.
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 23-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Phan et al. (Cancer Gene Ther. Vol. 27 No. 3-4, pages 235-245).
Phan et al. disclose the use of a recombinant Salmonella typhimurium VNP2009 shIDO-ST strain and an anti-PDL-1 antibody to treat colorectal adenocarcinomas (MC38) and colon tumors (CT26) in mice (see abstract and page 238). Consequently, Phan et al. anticipates all the limitations of the rejected claims.
Conclusion
No claim is allowed.
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/ROBERT A ZEMAN/Primary Examiner, Art Unit 1645 July 20, 2026
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