FINAL 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 .
Applicant’s amendment filed September 18, 2025 Is acknowledged. Claims 1-10, 13 and 16 have been canceled. Claims 11-12 and 14-15 have been amended and pending.
Maintained Rejections
Claim Rejections - 35 USC § 112
3. 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.
Enablement:
The claims 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 rejection is maintained for reasons of record. The amendments to claim 12 necessitated the inclusion of claims 12, 14, and 15. The rejection is repeated below, modified to address the limitations of claims 12, 14, and 15:
Factors to be considered in determining whether a disclosure enables one skilled in the art to make and use the claimed invention in its full scope without 9resorting to undue experimentation include: (1) the quantity of experimentation necessary; (2) the amount of direction or guidance presented; (3) the presence or absence of working examples; (4) the nature or complexity of the invention; (5) the state of the prior art; (6) the relative skill of those in the art; (7) the predictability or unpredictability of the art; and (8) the breadth of the claims.
See In re Wands, 8 USPQ2d. 1400 (Fed. Cir. 1988).
In the instant case, claim 11 is broadly drawn to methods for reducing or inhibiting LOX-1+ PMN-MDSC accumulation in a patient comprising administering to said patient a pharmaceutical composition comprising an antibody or functional antigen-binding fragment thereof that binds LOX-1 or an antibody or functional antigen-binding fragment thereof that binds to or inhibits the expression, activity, or activation of at least one of a list of 32 other protein targets, and assessing the patient for a decrease in LOX-1+ PMN-MDSC accumulation. The claim is extremely broad in that the patient population is not limited, and there are no structural features recited for any of the antibody products that bind to or inhibit expression, activity, or activation of LOX-1 or at least one of 33 diverse targets. Claims 12-14 start with the preamble of a method of detecting tumor size in a cancer subject, but also include a step of administering a pharmaceutical that reduces or inhibits ER stress in mammalian LOX-1+ neutrophils, LOX-1+ PMN or PMN-MDSC or reduces or inhibits LOX-1 expression on said cell populations. Since there is a method step of administering a pharmaceutical, these claims are also interpreted as a method of treatment, wherein the patient population is broadly recited as having a tumor of any type of cancer, and wherein the pharmaceutical is only limited by function, not structure.
The nature of the invention is thus complex and unpredictable, involving the effects of complex biological molecules on physiological systems. As was found in Ex parte Hitzeman, 9 USPQ2d 1821 (BPAI 1987), a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. This invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology”, Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). See also In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir.), cert. denied, 502 U.S. 856 (1991).
The amount of specific guidance and working examples in the specification is extensive with respect to the types of biomarkers expressed on the surface of PMN-MDSC from biological samples obtained from cancer patients, and the effects of LOX-1+ PMN/PMN-MDSC cells on suppressing T cell function. Figures 11K and 11L show the effects of sXBP1 inhibitor B-I09 on the THG-induced up-regulation of LOX-1 and T cell suppression in PMN from healthy donors. No specific guidance or working examples are provided with respect to administering a therapeutic agent to treat cancer. However, the specification makes it clear that the point of reducing or inhibiting LOX-1+ PMN-MDSC accumulation in a patient is to treat cancer. The specification does not appear to suggest any other reason to administer the recited antibody products to a patient to reduce or inhibit LOX-1+ PMN-MDSC accumulation.
Historically, the state of the art has indicated that the treatment of cancer in general is at most unpredictable, as underscored by Gura (Science, v278, 1997, pp. 1041-1042) who discusses the potential shortcomings of potential anti-cancer agents including extrapolating from in vitro to in vivo protocols, the problems of drug testing in knockout mice, and problems associated with clonogenic assays. Indeed, since formal screening began in 1955, thousands of drugs have shown activity in either cell or animal models, but only 39 that are used exclusively for chemotherapy, as opposed to supportive care, have won approval from the FDA (page 1041, 1st column) wherein the fundamental problem in drug discovery for cancer is that the model systems are not predictive. Moreover, those of skill in the art recognize that in vitro assays and or cell culture- based assays are generally useful to observe basic physiological and cellular phenomenon such as screening the effects of potential drugs. However, 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 human diagnostic 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, p4) 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). Further, Dermer (Bio/Technology, 1994, 12:320) teaches that, "petri dish cancer" is a poor representation of malignancy, with characteristics profoundly different from the human disease. In addition, 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. Zips et al. (2005, In Vivo 19:1-8) indicate that while in vitro assays are useful as a first step, a cancer therapeutic must be evaluated in vivo for therapeutic benefit (abstract, top of p. 3, p. 6 conclusion). An editorial in Nature Biotechnology in 2013 reviews similar studies and arrives at the same conclusions (2013, Nature Biotechnology 31:85). Clearly it has been well known in the art over the past few decades 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.
Due to the large quantity of experimentation necessary to determine how to achieve the recited effects in patients, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to the same, the complex nature of the invention, the contradictory state of the prior art, the unpredictability of the effects of any new therapeutic agent on an in vivo system based on preliminary in vitro results, and the breadth of the claims which fail to recite structural limitations of the recited therapeutic agents or the type of cancer being treated, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
Applicant’s Arguments
Applicant argues that the claims have been amended to limit the claims to treating the patients with antibodies that bind to LOX-1, sXBP1, or ARGI. Applicant argues that inhibition of each of the recited targets have been shown to reduce the accumulation of PMN-MDSCs and cites figures 11K, 11L, 11D, and 10G-10I to support this argument. Applicant argues that it would be routine experimentation for the skilled artisan to use the method to show that this specific sXCP1 inhibitor reduces PMN levels to test whether other sXBP1 inhibitors, LOX-1 antibodies, and other ARGI inhibitors would also reduce PMN levels. Additionally, as set forth in the December 13, 2024 FOA response, a reduction in PMN-MDSC accumulation is effective for the treatment of cancer. Applicant argues that the specification provides an exemplary method for testing these inhibitors, and the claim is limited to inhibitors of specific genes, and therefore, undue experimentation would not be required to make or use the claimed invention.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive.
In response to Applicant’s argument that the claims have been limited to specific genes and treating the patients with antibodies that bind the specific genes, as noted in the rejection above, the specification provides no guidance regarding treating any cancer with the claimed antibodies that bind LOX-1, sXBP1, or ARGI. Although the specification demonstrates that exemplary inhibitors of the claimed genes suppress the activity of PMN-MDSC, the specification does not provide a nexus between these results and the treatment of any cancer.
The claims are extremely broad in that they encompass all types of cancers. The specification supports the breadth of the claims by teaching that the term "cancer" or "tumor broadly encompasses any form of cancer, including hematological cancers, e.g., leukemia, lymphoma, myeloma, bone marrow cancer, and epithelial cancers, including, without limitation, breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, endometrial cancer, esophageal cancer, stomach cancer, bladder cancer, kidney cancer, pancreatic cancer, cervical cancer, head and neck cancer, ovarian cancer, melanoma, leukemia, myeloma, lymphoma, glioma, Non-Hodgkin's lymphoma, leukemia, multiple myeloma and multidrug resistant cancer. However, the cancer treatment art is unpredictable. As stated in the rejection, the level of unpredictability for the cancer treatment art is quite high. The art teaches that the unpredictability of the cancer treatment art is in part due to the fact that it is difficult to extrapolate from in vitro to in vivo protocols. While in vitro assays and cell culture-based assays are generally useful to observe basic physiological and cellular phenomenon, clinical correlation are generally lacking. The in vivo environment is extremely complex compared to the very narrowly defined and controlled conditions of the in vitro environment, and thus, in vitro assays do not permit a single extrapolation to human treatment with any reasonable degree of predictability. Although the specification provides in vitro evidence of the expression of the claimed markers on the surface of PMN-MDSC, as well as the effects of sXBP1 inhibitor B-109 on the THG-induced upregulation of LOX-1 and T cell suppression in PMN from healthy donors, this is not predicative of treating any cancer with any antibody that binds to LOX-1, sXVP1, or ARGI. Given the unpredictable art of treating tumors in vivo using antibody therapy, compounded by the numerous types of cancers, one of skill in the art could not predictably treat all of the encompassed solid cancer types by administering any of the thousands of encompassed antibodies that binds to LOX-1, sXVP1, or ARGI.
Due to the large quantity for experimentation necessary to determine the specific agents for each tumor, the lack of directions and guidance presented in the specification regarding the same, the lack of working example directed to the same, the complex nature of the invention, the unpredictability in the state of the art, and the breadth of the claims, undue experimentation would be required for the skilled artisan to make and use the claimed invention commensurate in scope with these claims.
Written Description:
The claims 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 claims recite administration of a pharmaceutical that reduces or inhibits ER stress in mammalian LOX-1+ neutrophils, LOX-1+ PMN pr PMN-MDSC, or inhibits LOX-1 expression on said cell populations. This is a genus defined solely by function.
The specification indicates that treatment with ROS scavenger N-acetylcysteine and inhibitor of Arg1 Nor-NOHA decreased LOX-1 expression as recited by the claims (e.g., Example 10). Treatment with B-I09 appears to combat the up-regulation of LOX-1 expression caused by ER stress inducers THG and DTT, but it is unclear if B-I09 reduces LOX-1 expression in the absence of THG and DTT. Accordingly, only a couple of therapeutic agents appear to be associated with the required suppression of LOX-1 expression.
To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the claim is a function. There is not even identification of any particular portion of the structure that must be conserved. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states 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).
With the exception of ROS scavenger N-acetylcysteine and inhibitor of Arg1 Nor-NOHA, the skilled artisan cannot envision the detailed chemical structure of the encompassed therapeutic agents, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only ROS scavenger N-acetylcysteine and inhibitor of Arg1 Nor-NOHA, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Applicant’s Arguments
Applicant argues that the claims have been amended to limit the claims to treating the patients with antibodies that bind to LOX-1, sXBP1, or ARGI. Applicant argues that the specification teaches that treatment with inhibitors or antibodies that binds to these specific targets. Applicant submits hat the claims as amended are fully described.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive.
In response to Applicant’s argument that the claims have been limited to specific genes and treating the patients with antibodies that bind the specific genes, as noted in the rejection above, the specification provides no guidance regarding treating any cancer with the claimed antibodies that bind LOX-1, sXBP1, or ARGI. Although the specification demonstrates that exemplary inhibitors of the claimed genes suppress the activity of PMN-MDSC, the specification does not provide a nexus between these results and the treatment of any cancer. Thus, the agents encompassed by the claims have no correlation between their structure and function. Further, the few species disclosed are not deemed to be representative of the genus encompassed by the claims. The claims encompass any antibody that binds to LOX-1, sXVP1, or ARGI. These antibodies have the required function of binding to a particular targeting and treating cancer. However, the specification provides no guidance regarding a species that has the claimed function. Thus, demonstrating the effects of sXBP1 inhibitor B-109 on the THG-induced upregulation of LOX-1 and T cell suppression in PMN from healthy donors is not deemed to be representative of the genus of agents that must inhibit a particular target and treat cancer.
Conclusion
No claims are allowed.
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.
Conclusion
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/VANESSA L FORD/ Supervisory Patent Examiner, Art Unit 1674