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 .
Claim 1 filed March 17, 2023 is under examination.
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.
Claim 1 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The claimed invention embraces a method of treating resistance to Gefitinib in colon cancer comprising an inhibitor against CD133 a CD133 gene to a subject resistant to Gefitinib, wherein the inhibitor is a peptide, a compound, or an antibody against the CD133 protein.
The specification teaches that the candidate exhibiting an activity of inhibiting gene expression or a protein function, obtained by the screening method of the present invention, may be a candidate for a resistant cancer therapeutic agent. The candidate for a therapeutic agent against cancer resistant to an EGFR-targeting agent serves as a leading compound in the development of a therapeutic agent against resistance to an EGFR-targeting agent, and modifies and optimizes the structure of the leading compound to exhibit an effect of inhibiting the CD133 gene or the function of a protein expressed therefrom, thereby developing a novel therapeutic agent against cancer resistant to an EGFR-targeting agent. The claimed invention encompasses all peptide, a compound, or an antibody against the CD133 protein.
The instant specification has not provided a structure that correlates with inhibiting CD133. A skilled artisan understands that their may be variability in the broadly claimed CD133 inhibitors used in the claimed method. This is evidenced by Mak et al (Am J Pathol. 2014 May;184(5):1256–1262). Mak et al teach that one concern of using drugs or molecules that target CD133 in cancer stem and progenitor cells is the result of retinal degeneration and vision loss as mouse models and patients carrying certain CD133 gene mutations acquire progressive retinal degeneration and blindness. However, it is possible that small-molecule inhibitors targeting CD133 may be blocked from CD133+ retinal progenitor cells because of the blood-ocular barrier, thus preventing retinal degeneration and loss of vision and on the basis of the current data, we propose that targeting CD133 would be a novel and viable approach for cancer treatment, in part by inhibiting various tumor vascularization mechanisms and abolishing the CSCs simultaneously. Although we, and others, have demonstrated that silencing CD133 using RNA interference results in a significant reduction in tumor vascularization and size, further experiments using anti-CD133 blocking antibodies or HDAC6 small-molecule inhibitors in xenograft mouse models are warranted. These in vivo studies in mouse models are particularly important to investigate the impact of targeting CD133 in CD133+ normal stem and progenitor cell populations, such as those in the retina, for potential adverse effects (page 1260).
With respect to preventing resistance to an EGFR-targeting agent in colon cancer, the CD133 expression level is higher than that of the normal control sample it can be determined that a patient has resistance to an EGFR-targeting agent (page 12). The subject embraces a subject who has colon cancer or does not have colon cancer. CD133 is highly expressed in cancer cells with resistance to an EGFR-targeting agent. The applicant contemplates the method of preventing in a genus of subjects, but does not describe the method steps to carry out the claimed method. If CD133 is expressed at a certain level than resistance has already occurred and preventing resistance is not possible. The applicant does not provide method steps for how to identify a subject that is susceptible to resistance to an EGFR-targeting agent in colon cancer before it has already happened. There is no description for what CD133 expression level has to be observed for the skilled artisan to determine that the subject has to be administered the inhibitor. Note that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See Enzo Biochem., 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). See also MPEP §2163.
In view of the foregoing, it is clear that the instant specification fails to convey that the inventors had possession of the genus of inhibitors or a method of treating all tumors as claimed in claim 1 as of the effective filing date sought in the instant case.
Claim Rejections - 35 USC § 103
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 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.
Claim 1 is rejected under 35 U.S.C. 103(a) as being anticipated by Haber et al (US 10,596,162 B2 published March 24, 2020) in view of Van Orden et al. (US 2010/0040637) in view Jang et al (Cancer Letters, Volume 389, 28 March 2017, pages 1-10).
Claim 1 is drawn a method of treating resistance to Gefitinib in colon cancer, the method comprising administering an inhibitor against a CD133 gene to a subject resistant to Gefitinib, wherein the inhibitor is a peptide, a compound, or an antibody against the CD133 protein.
Haber et al teach a method of treating cancer patients that have developed a resistance to gefitinib. Haber et al teach that administering a composition comprising an irreversible epidermal growth factor receptor (EGFR).(see the Abstract). Haber et al teach that epithelial cancers to include colon cancer are characterized by abnormal accelerated growth of epithelial cells (see column 1). Haber et al have discovered that irreversible EGRFs are effective in treating cancer patients that no longer respond to gefitinib therapies. Haber et al teach that the EGRFs of the invention can be used in combination therapies (column 7).
Haber et al do not teach the use of CD133 inhibitors in a method of treating gefitinib resistant cancer patients.
Van Orden et al teach methods and compositions for detecting and treating diseases including colon cancer with differential expression of prominin-1(CD133) in disease cells compared to healthy cells (see the Abstract). Van Orden et al teach the nucleic acid molecules are also useful for monitoring the effectiveness of modulating compounds or agents on the expression or activity of the prominin-1 gene in clinical trials or in a treatment regimen. Thus, the gene expression pattern can serve as a barometer for the continuing effectiveness of treatment with the compound, particularly with compounds to which a patient can develop resistance. The gene expression pattern can also serve as a marker indicative of a physiological response of the affected cells to the compound. Accordingly, such monitoring would allow either increased administration of the compound or the administration of alternative compounds to which the patient has not become resistant (page 27). Van Orden et al teach that the present invention further provides antagonists to prominin-1 protein or peptides and pharmaceutical compositions that comprise the antagonist and a suitable carrier. The antagonists may be used for treating the disease. Preferably, the antagonist is an antibody that specifically binds to a prominin-1 protein or peptide. The antibody may be used alone or in combination with another therapeutic agent (e.g., as an antibody drug conjugate or a combination therapy). The antagonist may be a small molecule that inhibits the function or levels of prominin-1, or an inhibitory nucleic acid molecule, such as an RNAi or antisense molecule against a prominin-1 nucleic acid (page 2). Jang et al teach that cancer stem cells (CSCs) are small subpopulation of cells within tumors that drive chemoresistance and tumor recurrence in various cancers. We characterized CSCs in primary HCC and identified CD133 as a CSC surface marker. CD133+ HCC cells displayed more stem cell-like properties, tumor spheroid-forming ability, chemoresistance, migration ability, and tumorigenic capacity than CD133- HCC cells. Jang et al teach that results strongly indicate that CD133 facilitates CSC-like properties by stabilizing EGFR-AKT signaling in HCC. It might therefore be feasible to use CD133 as a novel target to sensitize HCC cells that manifest resistance to EGFR-targeted therapy.
Jang et al teach that CD133 is a 5-transmembrane glycoprotein expressed by a subpopulation of the hematopoietic stem cells originating from fetal liver and bone marrow. It is also commonly known in humans and rodents as Prominin 1 (PROM1). CD133 is considered a surface marker of CSCs in cancers of the brain, colon, pancreas, prostate, and liver. Previous work showed that CD133 is a highly expressed marker of liver cancer stem cells (LCSCs). A high level of CD133 expression was an independent prognostic indicator for survival and tumor recurrence in patients with HCC. Interestingly, CD133+ HCC cells exhibited chemoresistance through activation of the AKT/PKB and Bcl-2 pathway. The epidermal growth factor receptor (EGFR) is one of the receptor tyrosine kinases (RTKs), which play roles in the control of cell proliferation, migration, and differentiation in various types of cancer. Because of the specification of EGFR, the dysregulation of EGFR is involved in many cancer types. EGFR overexpression, which occurs in 40–70% of human HCC, is related to tumorigenesis. Therefore, many studies attempt to target EGFR, and EGFR antagonists have been developed to treat patients with HCC. EGFR antagonists have shown effects on human and rat HCC cells; however, the EGFR inhibitors gefitinib, cetuximab, and erlotinib have not shown any meaningful effects in patients with advanced HCC. Jang et al teach that CSCs have displayed increased drug resistance in various cancer types. We therefore investigated cell viability after treatment with established chemotherapeutic drugs. The overall numbers of cells were dramatically decreased by the treatments (Fig. 2-A); however, the numbers of CD133+ cells increased following treatments with the chemotherapeutic drugs. Jang et al teach that their research approach is to secure a novel strategy to improve the efficacy of EGFR antagonists in HCC, because we found that the stability of EGFR expression is controlled by the expression status of CD133. Our data clearly suggest that CD133 is upstream of the EGFR-related signal cascade in HCC, because CD133 knockdown down regulated EGFR expression, but EGFR knockdown did not affect CD133 expression [Fig. 3-E]. The RTK assay, expression levels of EGFR and IGF-R was increased in CD133+ cells. From these result and other studies, we suggest that CD133 acts as a regulator of EGFR and that it gives rise to drug resistance for EGFR-targeting anticancer drugs. If we develop inhibitors of CD133 expression, we can look forward to synergistic efficacy between EGFR antagonists and CD133 inhibitors for liver cancer therapy. In this study, we tried to elucidate the mechanisms of CD133-induced chemoresistance in HCC. Through that process, we demonstrated that CD133 could promote HCC chemoresistance and migration by stabilizing EGFR expression as well as EGFR-AKT signaling in HCC. Hence, targeting the regulation of CD133 expression could represent a promising therapeutic strategy for overcoming chemoresistance and tumorigenesis in HCC.
It would have been prima facie obvious at the time the invention was filed, that one of ordinary skill in the art would modify the method of Haber et al to include the CD133 inhibitors taught by Van Orden et al because Van Orden et al teach that the gene expression pattern can serve as a barometer for the continuing effectiveness of treatment with the compound, particularly with compounds to which a patient can develop resistance and Jang et al teach that results strongly indicate that CD133 facilitates CSC-like properties by stabilizing EGFR-AKT signaling in HCC. It might therefore be feasible to use CD133 as a novel target to sensitize HCC cells that manifest resistance to EGFR-targeted therapy. Jang et al further teach that their research approach is to secure a novel strategy to improve the efficacy of EGFR antagonists in HCC (epithelial cancer), because we found that the stability of EGFR expression is controlled by the expression status of CD133.
The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; B/E Aerospace, Inc. v. C&D Zodiac, Inc., 962 F.3d 1373, 1379, 2020 USPQ2d 10706 (Fed. Cir. 2020); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atl. & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950). "[I]t can be important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does." KSR, 550 U.S. at 418, 82 USPQ2d at 1396. If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art.
Status of Claims
6. No claims allowed.
Conclusion
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/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674