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 .
Priority
This application claims priority to U.S. provisional applications 63/322,368, filed on 22 March 2022. The effective filing date is 22 March 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 22 January 2024 is being considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-20 are pending and the subject of this office action.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Specifically, the applicant refers to colored figures in the description of figures 1, 4, 6, 8, 9, 13, and 15. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 112a
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 5-8 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 claims 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.
Claims 5-8 are drawn to a method of treating kidney cancer in a subject through the administration of a recombinant antibody, wherein the complementary-determining regions 1, 2 and 3 of the heavy chain variable region share at least 80 % sequence identity to SEQ ID NO: 8, 9, and 10, respectively, or wherein the complementary-determining regions 1, 2 and 3 of the light chain variable region share at least 80 % sequence identity to SEQ ID NO: 14, 15, and 16, respectively. The claims encompass a genus of heavy and light chain variable regions comprising at least 20% variability (≤ 80% identity), as the claims also teach the use of fragments of the CDRs, in the both the heavy and light chain variable regions which are claimed to specifically bind human chemerin and treating subjects having kidney cancer.
The instant disclosure, however, does not provide an adequate number of species of the claimed genus nor does the disclosure provide a structure-function correlation that would allow for an ordinarily skilled artisan to envision what variation can occur in the heavy and light chains, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
The current disclosure discusses anti-chemerin antibodies derived from an antibody, comprising VH and VL regions defined in Figure 18. This antibody, with 100% sequence identity in the CDR regions of the heavy and light chain variable regions, represents the antibody that applicant was in possession of at the time of filing. It is noted that there would be support for 100% identity of the full complement of the six CDRs together with some percentages of identity in the framework region that would have been predictable.
The state of the art around the effective filing date of the claimed invention also does not provide an adequate number of species of the claimed genus or the necessary structure-function correlation. Rather, the art demonstrates that antibody functionality was known to depend on the entire antibody structure, particularly a full complement of six CDRs. Chiu ML, et al. (2019) Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel). Dec 3;8(4):55 teaches that the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). Here, Chiu teaches that the interaction between the heavy and light chain variable domains effects the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably determine which amino acids in which CDR regions could be modified such that the antibody would still perform the function of selectively binding to chemerin and being able to treat a subject who has kidney cancer.
Rabia L, et al. (2018) Understanding and overcoming tradeoffs between antibody affinity, specificity, stability, and solubility. Biochem Eng. J. 15(137); 365-374 discusses the challenges with optimizing antibody properties and states “the most important antibody properties relate to their natural functions, such as their high binding affinity and specificity mediated by their complementarity-determining regions (CDRs) within the variable regions... Other key natural antibody properties include their effector functions — such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC)- which are mediated by their constant regions” (page 2, paragraph 1). Rabia further teaches that “most antibodies identified during the initial discovery process are not suitable for therapeutic use and require additional optimization. For example, the binding affinities of some lead antibodies are not high enough for therapeutic applications” (page 2, paragraph 3). Rabia goes on to state that “natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity...antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations” (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that “a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that co-optimize multiple antibody properties” and that “future efforts will also need to improve structural predictions of antibody CDRs — especially the long and highly variable heavy chain CDR3-to accurately predict CDR mutations that are beneficial to different antibody properties” (page 9, paragraph 4 — page 10 paragraph 2).
Based on the teachings of Rabia, introducing mutations in antibody structure, particularly in the CDR regions, is not predictable and requires experimentation following mutation to ensure that binding affinity is maintained and a stable antibody is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and demonstrated how these methods are not robust enough yet to yield predictable results. This teaching demonstrates that modifications to the sequences of the claimed invention could result in an antibody that is not suitable for binding to chemerin or treating kidney cancer.
Overall, it is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species of the claimed genus at the time of filing. Specifically, it is not evident that applicant was in possession of a representative number of antibody species with variation in the CDRs, which are the known binding regions of the antibody, that performed the claimed function. Additionally, there is no disclosed or art recognized relationship between antibody structure and function which would allow for the predictable modification of the claimed antibody with up to 20% variance anywhere in the structure, particularly in the CDRs, while maintaining the claimed functions. Therefore, the instant claims are found to not meet the written description requirement.
Claims 5 and 7 refer to antibodies that are comprised of variable regions comprising CDRH1 (SEQ ID NO: 8), CDRH2 (SEQ ID NO: 9), and/or CDRH3 (SEQ ID NO: 10) and/or CDRL1 (SEQ ID NO:14), CDRL2 (SEQ ID NO: 15), CDRL3 (SEQ ID NO:16). As taught by Chiu (see above), an antibody binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. It is not taught in the instant application or the prior art how one would maintain functional and biochemical characteristics of the antibody while not maintaining the six CDRs.
Claim Rejections - 35 USC § 112a
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 14-20 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 claims contain 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 considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Regarding the nature of the invention, the invention describes a method for kidney cancer through the administration of a chemerin inhibitor. However, claims 14-20 describe an antibody or a nucleic acid sequence / expression vector encoding said antibody, with CDRH1, CDRH2, and CDRH3 comprised of sequences or fragments thereof sharing at least 80% identity to SEQ ID NOs: 8, 9, and 10, respectively. These claims have no functional limitations other than the inherent characteristics defined by the CDRs of the working example listed in SEQ ID NOS: 3, 8, 9, and 10. However, the scope of the claims extend beyond the function defined by the CDR/VH sequences, due to the allowed 20% sequence variation or fragmentation as written in the claims.
As taught by Rabia (see 112a written description rejections), the prior art is quite clear that the addition of mutations to the structure of an antibody, specifically the CDRs, is not predictable and requires significant experimentation following mutation to ensure that binding affinity is maintained and a stable antibody is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and demonstrated how these methods are not robust enough yet to yield predictable results. This teaching demonstrates that modifications to the sequences of the claimed invention could have unpredictable results and could result in functional or biochemical properties, which the current disclosure has not properly enabled.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-4, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Tümmler C, et al. (2017) Inhibition of chemerin/CMKLR1 axis in neuroblastoma cells reduces clonogenicity and cell viability in vitro and impairs tumor growth in vivo. Oncotarget. Jul 27;8(56):95135-95151 (herein Tümmler) in view of Kumar JD, et al. (2016) The role of chemerin and ChemR23 in stimulating the invasion of squamous oesophageal cancer cells. British Journal of Cancer. (114):1152-1159 (herein Kumar) and Krawczyk KM, et al. (2017) Papillary renal cell carcinoma-derived chemerin, IL-8, and CXCL16 promote monocyte recruitment and differentiation into foam-cell macrophages. Lab Invest. Nov;97(11):1296-1305 (herein Krawczyk).
In regard to claim 1 Tümmler teaches that several forms of cancer are associated with increased levels of chemerin, and have been shown to promote tumorigenesis in glioblastoma, gastric cancer, squamous esophageal cancer and squamous cell carcinoma of the tongue (introduction paragraph 3). Additionally, it is shown that levels of chemerin receptors (CMKLR1, and CCRL2) are also elevated in neuroblastoma when compared to neurofibroma and neural crest cells, and that a correlation exists between high expression GPR1 or CMKLR1 and decreased overall survival probability when examining two neuroblastoma gene expression cohorts (results: High CMKLR1 and GPR1 expression predict poor overall survival probability in neuroblastoma, Figure 1, and supplementary figure 1). They also teach that blocking the interaction between chemerin and CMKLR1, through the use of a small molecule CMKLR1 antagonist, reduces the clonogenicity and cell viability of neuroblastoma cell in vitro, and impairs tumor growth in xenografted mice (abstract, results: CMKLR1 inhibition reduces the cell viability and clonogenicity of neuroblastoma cells, results: early and prolonged CMKLR1 inhibition impairs neuroblastoma growth in vivo, and figures 6 and 7). Tümmler also teaches that CMKLR1 mediates the majority of chemerin functions (introduction paragraph 3).
Tümmler does not teach the disruption of the chemerin-CMKLR1 as a method for treating kidney cancer.
Krawczyk teaches that chemerin, IL-8, and CXCL16 are overexpressed and secreted in papillary renal cell carcinoma (figure 3 and discussion paragraph 8). Krawczyk further teaches that these secreted proteins, either in combination or individually, attract human monocytes in vitro (results: Cultured Primary Human pRCC Cells Secrete Factors that Attract Monocytes, and figure 4). Additionally, they teach that the conditioned medium from these cell cultures is capable of inducing a shift in monocytes towards the anti-inflammatory M2 macrophage phenotype, and that continued culture of these cells in the cultured medium resulted in a further shift in phenotype resembling foamy macrophages (results: conditioned medium from human primary pRCC cells induces a phenotypic switch and lipid accumulation in human monocytes and figure 5).
Kumar teaches inhibition of the chemerin-CMKLR1 interaction, either by targeting chemerin, through the use of siRNA or an immuno-neutralizing antibody, or by targeting CMKLR1, through the use of siRNA or a small molecule antagonist (results: Chemerin released by myofibroblasts acts on OE21 cells). Kumar also teaches that inhibition of the chemerin-CMKLR1 interaction, through the means mentioned above, limits the migration/invasion of squamous oesophageal cancer cells (conclusion).
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to use chemerin inhibitors as a method to treat kidney cancer.
As taught by Tümmler, overexpression of chemerin and its receptors is a hallmark of certain forms of cancer. Tümmler also shows that inhibition of the chemerin-CMKLR1 interaction impairs neuroblastoma tumor growth in a xenografted mouse model. This study clearly teaches the inhibition of the chemerin-CMKLR1 interaction as a method to treat cancer. The need to inhibit chemerin in kidney cancer is taught by Krawczyk, who teaches that certain forms of kidney cancer, such as papillary renal cell carcinoma, have elevated chemerin levels, and that chemerin directly influences the activity of the cancer cells. This study clearly provides the motivation to inhibit chemerin in the treatment of kidney cancer. Kumar teaches the use of chemerin-specific inhibitors, as opposed to targeting CMKLR1, through the use of neutralizing antibodies and siRNA. Due to the prior art presented, there would have been a reasonable expectation of success associated with a method of treating kidney cancer with chemerin inhibitors.
In regard to claims 2-4 and 9, Tümmler, Krawczyk, and Kumar teach the use of chemerin inhibitors to treat kidney cancer as described for claim 1.
Kumar further teaches the use of anti-chemerin antibodies and siRNA to inhibit the activity of chemerin (results: Chemerin released by myofibroblasts acts on OE21 cells). Although, Kumar teaches the use of a mouse mAb, humanization of mouse antibodies has become routine as taught by Khantasup et al (Monoclonal Antibodies in Immunodiagnosis and Immunotherapy, 2015, 34(6): 404-417). Khantasup et al teaches: “The standard method involves grafting mouse complementary-determining regions (CDRs) onto human framework regions (FRs). The critical objective is to prevent loss on antigen-binding affinity due to loss of original CDR conformations after CDR grafting. Several factors play a role in preventing loss of affinity, including proper selection of human template, compatibility between mouse CDRs and huma FRs, and retention or back mutation of mouse FR residues at positions that maintain original CDR conformation” (page 405 paragraph 1 and page 407 column 2 paragraph 4).
Claims 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Tümmler C, et al (2017) Inhibition of chemerin/CMKLR1 axis in neuroblastoma cells reduces clonogenicity and cell viability in vitro and impairs tumor growth in vivo. Oncotarget. Jul 27;8(56):95135-95151 (herein Tümmler), Kumar JD, et al (2016) The role of chemerin and ChemR23 in stimulating the invasion of squamous oesophageal cancer cells. British Journal of Cancer. (114):1152-1159 (herein Kumar) and Krawczyk KM, et al (2017) Papillary renal cell carcinoma-derived chemerin, IL-8, and CXCL16 promote monocyte recruitment and differentiation into foam-cell macrophages. Lab Invest. Nov;97(11):1296-1305 (herein Krawczyk) in view of Watts SW, et al (2018) The chemerin knockout rat reveals chemerin dependence in female, but not male experimental hypertension. FASEB J. Jun 15;32(12):6596-6614 (herein Watts).
Tümmler, Kumar, and Krawczyk teach the use of chemerin inhibitors (antibodies, small moleculs, and siRNA) to treat kidney cancer as described for claim 1.
Tümmler, Kumar, and Krawczyk do not the use of the CRISPR/cas endonuclease (Cas)9 system for the treating kidney cancer. These deficiencies are taught by Watts as described below.
Watts teaches the use of CRISPR/cas-9 system to engineer a chemerin-knockout rat model (abstract). This study teaches the use of single-guide RNA against the Rarres2 gene (materials and methods: Construction of chemerin WT and KO rat). Although, this study was related to the rat chemerin and does not teach the gRNA mentioned in claim 11 (SEQ ID NO: 17-40), the design of gRNA is trivial, as there are numerous publicly available resources to aid in their design. One such tool, Benchling (benchling.com), which was available prior to the submission of the instant application was able to predict the gRNA corresponding to numerous gRNA sequences listed in the instant application. One such example is SEQ ID NO: 17, which targets exon 1 of the Rarres2 gene. Use of this gRNA would be obvious to one of average skill in the art, as this gRNA was predicted to be the most likely to be effective for targeting exon 1 of Rarres2. This gRNA had the highest on-target score, 72.1, and off-target score, 44.0, of all possible sites within exon 1, using a 20-nt target sequence length.
Claims 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Tümmler C, et al (2017) Inhibition of chemerin/CMKLR1 axis in neuroblastoma cells reduces clonogenicity and cell viability in vitro and impairs tumor growth in vivo. Oncotarget. Jul 27;8(56):95135-95151 (herein Tümmler) in view of Kumar JD, et al (2016) The role of chemerin and ChemR23 in stimulating the invasion of squamous oesophageal cancer cells. British Journal of Cancer. (114):1152-1159 (herein Kumar) and Krawczyk KM, et al (2017) Papillary renal cell carcinoma-derived chemerin, IL-8, and CXCL16 promote monocyte recruitment and differentiation into foam-cell macrophages. Lab Invest. Nov;97(11):1296-1305 (herein Krawczyk) and US20090234202 A1 (herein Goix).
Goix teaches a highly sensitive method for detection of molecules in which a biological sample is collected from a subject, compared to reference ranges for normal/abnormal states, and treatment is selected and administered based on the levels relative to the reference range ([0468], [0342], and [0113]). This disclosure provides chemerin as a representative marker for inflammation and provides the detection of kidney cancer as a potential embodiment ([0118], [0131], and [0433]).
Goix does not teach the administration of anti-cancer agent if chemerin levels are outside the normal reference range.
Tümmler, Krawczyk, and Kumar teach the use of chemerin inhibitors as an anti-cancer agent to treat kidney cancer in patients with elevated chemerin levels as described for claim 1.
It would be prima facie obvious to one of ordinary skill in the art to combine a method for detecting elevated levels of chemerin with an anti-cancer agent, such as a chemerin inhibitor, to subjects that show elevated chemerin levels.
Allowable Subject Matter
SEQ ID NO: 3 of claims 6 and 15 is free of prior art.
Claims 14-20 are being rejected due to 112a rejections, but would be allowable if rewritten to avoid triggering enablement rejections (see MPEP 2164). Additionally, the applicant should be aware that any claim regarding SEQ ID NO: 4 must include functional limitations to avoid possible 102 rejections, as it has been defined in prior art (i.e the variable light region (SEQ ID NO: 4) must be linked to the heavy variable region (SEQ ID NO: 3) or have other functional limitations to differentiate it from the prior art).
Conclusion
Claims 1-20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
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/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647