DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of invention Group II (claims 7-11, drawn to methods of treatment comprising administering an extracellular matrix-anticancer drug conjugate) in the reply filed on 10/13/2025 is acknowledged.
3. The election without traverse filed 10/13/2025 is acknowledged. Claims 7-11 are pending and under examination.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted 07/13/2022 and 04/17/2023 and the references cited therein have been considered, unless indicated otherwise.
Specification
5. The use of the terms MitoTracker Green, LysoTracker Green, and Leica which are trade names or a marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objection
6. Claims 7 and 10 are objected to because of the following informalities: Claim 7 and 10 refers to the conjugate of claim 1. However, claim 1 is a non-elected claim. The objection can be overcome if claim 7 and 10 refer to the actual conjugate in claim 1 in written form in its entirety, rather than just referring to the conjugate with the phrase “of claim 1”. Appropriate correction is required.
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.
Written Description
The following rejection is a written description rejection. This written description rejection has two issues. One issue regarding written description is the broadly claimed genus of cancers encompassed by the claimed invention and the other issue is the broadly claimed genus of “ suppressing anticancer drug resistance of tumor cells” encompassed by the claimed invention.
7. First, claims 7-9 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.
Claim 7-9 are drawn to a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the conjugate of claim 1; wherein the cancer is selected from the group consisting of liver cancer, kidney cancer, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, prostate cancer, brain cancer, stomach cancer, ovarian cancer, and uterine cancer; wherein the pharmaceutical composition increases apoptosis of tumor cells and suppresses anticancer drug resistance.
The specification teaches the conjugate includes an extracellular matrix (RGD-containing elastin-like polypeptide: REP) and an anticancer drug, the extracellular matrix includes an elastin-like polypeptide and an integrin receptor ligand, and the extracellular matrix and the anticancer drug are connected to each other by a linker (pages 2-3). The specification teaches the present disclosure may provide a pharmaceutical composition for cancer disease treatment including the extracellular matrix-anticancer drug conjugate as an active ingredient (page 6). The specification teaches he cancer disease may be selected from the group consisting of liver cancer, kidney cancer, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, prostate cancer, brain cancer, stomach cancer, ovarian cancer, and uterine cancer and the pharmaceutical composition may increase apoptosis of tumor cells and suppress anticancer drug resistance (page 6). The specification teaches human pancreatic cancer cells, human lung cancer cells, human liver cancer cells, human colorectal cancer cells, and human breast cancer cells, were treated with REP-doxorubicin and exhibited anticancer effects.
A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the conjugate of claim 1, does not meet the written description provision of 35 U.S.C. 112, first paragraph. The claims broadly encompass treating all cancers using the aforementioned method. The specification teaches an effect of suppressing drug resistance in cancer cells exhibiting resistance to doxorubicin is confirmed, the extracellular matrix (REP)- doxorubicin conjugate may be provided as an effective anticancer drug for cancer disease treatment and a pharmaceutical composition for suppressing drug resistance in cancer cells exhibiting anticancer drug resistance; however, this is not deemed to be predicative of treating all cancers using the claimed method. The claims broadly encompass the use of an extracellular matrix in combination with an anticancer agent to treat all cancers; however, the specification does not demonstrate that the conjugate has the function of treating all cancers. Therefore, the method has no correlation with its function. The specification is not deemed sufficient to reasonably convey to one skilled in the art that the inventors, at the time the invention was made, had possession of a method of treating all cancers with the claims method because the genus encompasses conditions which differ from those disclosed in etiologies, molecular mechanisms, diagnostic approaches, treatment modalities, and therapeutic endpoints. Furthermore, the recited genus encompasses conditions yet to be discovered and/or characterized; therefore, the skilled artisan cannot envision preventing all the contemplated diseases encompassed by the instant claims.
Furthermore, the specification provides only one example for suppressing drug resistance for one anticancer drug of one type of tumor cell: Table 3 demonstrated drug resistance in the doxorubicin-resistant MDA-MB-231 cells treated with REP-doxorubicin conjugate, however, this is not demonstrative of suppressing drug resistance for all anticancer drugs of all tumor cells.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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.)
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
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. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]. "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."). "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).
The state of the art regarding the use of ELP is discussed by Guo, et al (Guo, Y., Liu, S., Jing, D. et al. The construction of elastin-like polypeptides and their applications in drug delivery system and tissue repair. J Nanobiotechnol 21, 418 (2023). https://doi.org/10.1186/s12951-023-02184-8). Guo, et al. teach ELPS currently face problems that need to be solved. Guo further teach through genetic engineering methods, ELP can only be fused at the C-terminus or N-terminus of the protein, and the methods of modifying the protein are relatively limited. The fusion of therapeutic proteins with ELP may affect the biological activity of the drug, and further optimization is needed in the future to preserve the activity of therapeutic proteins (Conclusion, last paragraph)
Regarding the vast genus of tumors encompassed by the claims, while the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regards to treating all cancers with a single treatment is underdeveloped. In particular, there is no known combination of RGD-ELP and an anticancer agent that is effective against all cancer cell types. The cancer treatment art involves a very high level of unpredictability. Heppner et al. (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue. A key point made by Heppner et al. is that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult. Additionally, Bally et al. (US Patent No. 5,595,756) stated, "Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment limiting toxicities (See column 1). Sporn et al. (Chemoprevention of Cancer, Carcinogenesis, Vol. 21 (2000), 525-530) teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed. Sporn et al. also teach that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative cure.”
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al. (Cancer and Metastasis Reviews, 2000, 19: 167-172) indicate that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality (see p. 167, left column, 1st paragraph). Gura T (Science, 1997, 278(5340): 1041-1042) indicates that “the fundamental problem in drug discovery for cancer is that the model systems are not predictive at all” (see p. 1, 2nd paragraph). Furthermore, Gura T indicates that the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because the xenograft tumors don’t behave like naturally occurring tumors in humans—they don’t spread to other tissues, for example (see p. 2, 4th paragraph). Further, when patient’s tumor cells in Petri dishes or culture flasks and monitor the cells’ responses to various anticancer treatments, they don’t work because the cells simply fail to divide in culture, and the results cannot tell a researcher how anticancer drugs will act in the body (see p. 3, 7th paragraph). Furthermore, Jain RK (Scientific American, July 1994,58-65) indicates that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain (see p. 58, left most column, 1st paragraph). Further, Jain RK indicates that to eradicate tumors, the therapeutic agents must then disperse throughout the growths in concentrations high enough to eliminate every deadly cells…solid cancers frequently impose formidable barriers to such dispersion (see p. 58, bottom of the left most column continuing onto the top of the middle column). Jain RK indicates that there are 3 critical tasks that drugs must do to attack malignant cells in a tumor: 1) it has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, 2) exit from the vessel into the surrounding matrix, and 3) migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps (see p. 58, bottom of right most column). Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254) states that “The past three decades have seen spectacular advances in our understanding of the molecular and cellular biology of cancer. However, with a few notable exceptions, such as the treatment of chronic myeloid leukemia with imatinib, these advances have so far not been translated into major increases in long-term survival for many cancers. Furthermore, data suggest that the overall success rate for oncology products in clinical development is -10%, and the cost of bringing a new drug to market is over US$1 billion.” (see page 253, left column, the 1st paragraph). Hait further teaches “The anticancer drug discovery process often begins with a promising target; however, there are several reasons why the eventual outcome for a particular cancer target may be disappointing. For example, the role of the target in the pathogenesis of specific human malignancies may be incompletely understood, leading to disappointing results”, “First, many targets lie within signal transduction pathways that are altered in cancer, but, owing to the complex nature of these pathways, upstream or downstream components may make modulating the target of little or no value”; “Second, target overexpression is often overrated. There are some instances in which overexpression predicts response to treatment.”; and “Another confounding factor is that cancer is more than a disease of cancer cells, as alterations in somatic or germline genomes, or both, create susceptibilities to transformational changes in cells and in the microenvironment that ultimately cooperate to form a malignant tissue. The putative role of cancer stem cells in limiting the efficacy of cancer therapeutics is also an area of intense interest. Therefore, effective treatments may require understanding and disrupting the dependencies among the multiple cellular components of malignant tissues. Single nucleotide polymorphisms in genes responsible for drug metabolism can further complicate the picture by affecting drug pharmacokinetics; for example, as with the topoisomerase inhibitor irinotecan.”, for example, page 253, Section “Understanding the target in context”. Hait also teaches “Drug effects in preclinical cancer models often do not predict clinical results, as traditional subcutaneous xenografting of human cancer cell lines onto immunocompromised mice produces ‘tumours’ that fail to recapitulate key aspects of human malignancies such as invasion and metastasis. Several improvements have been made, including orthotopic implantation and use of mice with humanized haematopoietic and immune systems. Newer genetic mouse models can also allow analyses of tumour progression from in situ through locally advanced and, in certain cases, widespread metastatic disease. However, whether or not these models will more accurately predict drug activity against human cancer remains to be determined. Other alternatives, including three-dimensional tissue culture or xenografts of fresh human biopsy specimens onto immunocompromised mice, have the potential advantage of including the human microenvironment. However, these approaches have yet to prove their value relative to their cost.”, for example, page 253, Section “Predictive models”. Furthermore, Hait teaches that “It is now widely thought that biomarkers will drive a personalized approach to cancer drug development. The aim is that they will cut costs, decrease time to approval, and limit the number of patients who are exposed to potential toxicities without a reasonable chance of benefit — as exemplified by the development of imatinib and trastuzumab. However, recent attempts at repeating these successes in other cancer types have been less successful.”, for example, page 254, Section “Stratified/personalized medicine”. The challenges facing cancer drug development are further confirmed and discussed in Gravanis et al (Chin Clin Oncol, 2014, 3, pages 1 -5). Gravanis et al teach “The generic mechanism of action for cytotoxics made the prediction of which tumor types might respond to them very difficult, if not impossible, and necessitated a ‘trial and error’ approach against many different types of tumors.” and “The most prominent change in oncology drug development in the last 20 years has been the shift from classic cytotoxics to drugs that affect signaling pathways implicated in cancer, which belong to the so called ‘targeted therapies’.”, for example, page 1, Section “From cytotoxics to targeted therapies: how far are we from truly personalized medicine?”. Gravanis et al. further teach “Although constantly progressing, an understanding of cancer biology is far from complete. The ability to develop new compounds or generate biological data predictive of the clinical situation relies on good quality basic research data, although the complexity and constantly evolving biology of the tumor may be to blame for the frequent non-reproducibility of research results. Systemic biology approaches of the -omic type still generate largely incomprehensible, mostly due to their volume, analytical data, few pieces of which are currently actionable/drug-g-able. Finally, animal models of cancer are similarly unable to predict the clinical situation (for example, page 3, right column, the 2nd paragraph).
Beans (PNAS 2018; 115(50): 12539-12543) teaches that across cancer types, 90% of cancer deaths are caused not by the primary tumor but by metastasis. Beans teaches that although some drugs may shrink metastases along with primary tumors, no existing drugs treat or prevent metastasis directly (See page 12540). Beans states “Without a targeted approach, metastatic tumors often reemerge. “We shrink them, we send them back to their residual state, and they reenact those survival functions and retention of regenerative powers that made them metastasis-initiating cells in the first place” (See page 12540). Beans teaches that one of the major scientific challenges of studying metastatic disease is that different forms of cancer seem to metastasize through different mechanisms and the same form of cancer may metastasize differently in different subsets of patients (See page 12542). Of note, Beans states “It’s unlikely that one researcher is going to find one pathway that proves to be the key to metastasis” (See page 12542). Bean also teaches that translating many findings into therapies also presents unique hurdles in that it is difficult to measure the effectiveness of the therapy. Secondary tumors are often minuscule, and therefore, measuring success by tumor shrinkage may not work. Measuring the incidence of metastasis after treatment is also more difficult (See page 12542).
Given Bally et al teaching of treatment-limiting toxicities in clinical use; Sporn's teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype; Auerbach et al teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response; Gura's teaching that the models are unpredictable; Jain's teaching that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain; both Hait and Gravanis et al teaching various challenges facing cancer drug development, such as an understanding of cancer biology is far from complete, drug effects in preclinical cancer models often do not predict clinical results and many others; and Beans teachings that the field is highly underdeveloped with regards to preventing and treating cancer metastasis; the cited references demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers.
Taken together, the prior art recognizes RGD-TRAIL-ELP and RGD-ELP-C16 can treat breast cancer and liver cancer. However, the prior art does not teach any RGD-ELP and any anticancer agent can treat all cancers, and therefore, it is unclear if the claimed method would have the claimed function. Accordingly, one of skill in the art would conclude that the claimed invention encompasses a broad genus of cancers that may not respond to treatment with the claimed method. It should be noted that the specification has not demonstrated treating all cancers with the claimed method. Based on the teaching of the instant specification and the prior art one of skill in the art would not conclude that Applicant was in possession of the claimed method of treating the genus of cancers.
Consequently, the method for treating all cancers comprising administering an RGD-ELP and an anticancer agent, does not meet the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The applicant has not disclosed any species representative of the genus, which is highly variant. Applicant is reminded that Vas- Cath makes clear that the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is severable from its enablement provision. (See page 1115).
Second, claims 10-11 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.
Secondly, claims 10-11 are drawn to a method of suppressing drug resistance in a subject, comprising administering to the subject the conjugate of claim 1 as an active ingredient; wherein the drug resistance is anticancer drug resistance of tumor cells.
The specification teaches the conjugate includes an extracellular matrix (RGD-containing elastin-like polypeptide: REP) and an anticancer drug, the extracellular matrix includes an elastin-like polypeptide and an integrin receptor ligand, and the extracellular matrix and the anticancer drug are connected to each other by a linker (pages 2-3). The specification teaches the present disclosure may provide a pharmaceutical composition for cancer disease treatment including the extracellular matrix-anticancer drug conjugate as an active ingredient (page 6). The specification teaches he cancer disease may be selected from the group consisting of liver cancer, kidney cancer, lung cancer, breast cancer, colorectal cancer, pancreatic cancer, prostate cancer, brain cancer, stomach cancer, ovarian cancer, and uterine cancer and the pharmaceutical composition may increase apoptosis of tumor cells and suppress anticancer drug resistance (page 6). The specification teaches human pancreatic cancer cells, human lung cancer cells, human liver cancer cells, human colorectal cancer cells, and human breast cancer cells, were treated with REP-doxorubicin and exhibited anticancer effects. The specification teaches a pharmaceutical composition for suppressing drug resistance in cancer cells exhibiting anticancer drug resistance (page 8). The specification further teaches it was confirmed that the drug resistance overcoming effect appeared in the doxorubicin-resistant MDA-MB-231 cells treated with the REP-doxorubicin conjugate (page 17).
A method of suppressing drug resistance in a subject, comprising administering to the subject the conjugate of claim 1 as an active ingredient; wherein the drug resistance is anticancer drug resistance of tumor cells, does not meet the written description provision of 35 U.S.C. 112, first paragraph. The claims broadly encompass suppressing drug resistance for all anticancer drugs of all tumor cells using the aforementioned method. The specification teaches an effect of suppressing drug resistance in cancer cells exhibiting resistance to doxorubicin is confirmed, the extracellular matrix (REP)- doxorubicin conjugate may be provided as an effective anticancer drug for cancer disease treatment and a pharmaceutical composition for suppressing drug resistance in cancer cells exhibiting anticancer drug resistance; however, this is not deemed to be predicative of suppressing drug resistance for all anticancer drugs of all tumor cells using the claimed method. The claims broadly encompass the use of an extracellular matrix in combination with an anticancer agent to suppress drug resistance for all anticancer drugs of all tumor cells; however, the specification does not demonstrate that the conjugate has the function of suppressing drug resistance for all anticancer drugs of all tumor cells. Therefore, the method has no correlation with its function. The specification is not deemed sufficient to reasonably convey to one skilled in the art that the inventors, at the time the invention was made, had possession of a method of suppressing drug resistance for all anticancer drugs of all tumor cells with the claims method because the genus encompasses conditions which differ from those disclosed in etiologies, molecular mechanisms, diagnostic approaches, treatment modalities, and therapeutic endpoints. Furthermore, the recited genus encompasses conditions yet to be discovered and/or characterized; therefore, the skilled artisan cannot envision preventing all the contemplated diseases encompassed by the instant claims.
The state of the art regarding the use of ELP is discussed by Guo, et al (Guo, Y., Liu, S., Jing, D. et al. The construction of elastin-like polypeptides and their applications in drug delivery system and tissue repair. J Nanobiotechnol 21, 418 (2023). https://doi.org/10.1186/s12951-023-02184-8). Guo, et al. teach ELPS currently face problems that need to be solved. Guo further teach through genetic engineering methods, ELP can only be fused at the C-terminus or N-terminus of the protein, and the methods of modifying the protein are relatively limited. The fusion of therapeutic proteins with ELP may affect the biological activity of the drug, and further optimization is needed in the future to preserve the activity of therapeutic proteins (Conclusion, last paragraph)
Regarding the vast genus of tumors encompassed by the claims, while the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regards to suppressing drug resistance for all anticancer drugs of all tumor cells with a single treatment is underdeveloped. In particular, there is no known combination of RGD-ELP and an anticancer agent that is effective against suppressing drug resistance for all anticancer drugs of all tumor cells. The cancer treatment art involves a very high level of unpredictability. Heppner et al. (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue. A key point made by Heppner et al. is that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult. Additionally, Bally et al. (US Patent No. 5,595,756) stated, "Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment limiting toxicities (See column 1). Sporn et al. (Chemoprevention of Cancer, Carcinogenesis, Vol. 21 (2000), 525-530) teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed. Sporn et al. also teach that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative cure.”
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al. (Cancer and Metastasis Reviews, 2000, 19: 167-172) indicate that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality (see p. 167, left column, 1st paragraph). Gura T (Science, 1997, 278(5340): 1041-1042) indicates that “the fundamental problem in drug discovery for cancer is that the model systems are not predictive at all” (see p. 1, 2nd paragraph). Furthermore, Gura T indicates that the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because the xenograft tumors don’t behave like naturally occurring tumors in humans—they don’t spread to other tissues, for example (see p. 2, 4th paragraph). Further, when patient’s tumor cells in Petri dishes or culture flasks and monitor the cells’ responses to various anticancer treatments, they don’t work because the cells simply fail to divide in culture, and the results cannot tell a researcher how anticancer drugs will act in the body (see p. 3, 7th paragraph). Furthermore, Jain RK (Scientific American, July 1994,58-65) indicates that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain (see p. 58, left most column, 1st paragraph). Further, Jain RK indicates that to eradicate tumors, the therapeutic agents must then disperse throughout the growths in concentrations high enough to eliminate every deadly cells…solid cancers frequently impose formidable barriers to such dispersion (see p. 58, bottom of the left most column continuing onto the top of the middle column). Jain RK indicates that there are 3 critical tasks that drugs must do to attack malignant cells in a tumor: 1) it has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, 2) exit from the vessel into the surrounding matrix, and 3) migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps (see p. 58, bottom of right most column). Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254) states that “The past three decades have seen spectacular advances in our understanding of the molecular and cellular biology of cancer. However, with a few notable exceptions, such as the treatment of chronic myeloid leukaemia with imatinib, these advances have so far not been translated into major increases in long-term survival for many cancers. Furthermore, data suggest that the overall success rate for oncology products in clinical development is -10%, and the cost of bringing a new drug to market is over US$1 billion.” (see page 253, left column, the 1st paragraph). Hait further teaches “The anticancer drug discovery process often begins with a promising target; however, there are several reasons why the eventual outcome for a particular cancer target may be disappointing. For example, the role of the target in the pathogenesis of specific human malignancies may be incompletely understood, leading to disappointing results”, “First, many targets lie within signal transduction pathways that are altered in cancer, but, owing to the complex nature of these pathways, upstream or downstream components may make modulating the target of little or no value”; “Second, target overexpression is often overrated. There are some instances in which overexpression predicts response to treatment.”; and “Another confounding factor is that cancer is more than a disease of cancer cells, as alterations in somatic or germline genomes, or both, create susceptibilities to transformational changes in cells and in the microenvironment that ultimately cooperate to form a malignant tissue. The putative role of cancer stem cells in limiting the efficacy of cancer therapeutics is also an area of intense interest. Therefore, effective treatments may require understanding and disrupting the dependencies among the multiple cellular components of malignant tissues. Single nucleotide polymorphisms in genes responsible for drug metabolism can further complicate the picture by affecting drug pharmacokinetics; for example, as with the topoisomerase inhibitor irinotecan.”, for example, page 253, Section “Understanding the target in context”. Hait also teaches “Drug effects in preclinical cancer models often do not predict clinical results, as traditional subcutaneous xenografting of human cancer cell lines onto immunocompromised mice produces ‘tumours’ that fail to recapitulate key aspects of human malignancies such as invasion and metastasis. Several improvements have been made, including orthotopic implantation and use of mice with humanized haematopoietic and immune systems. Newer genetic mouse models can also allow analyses of tumour progression from in situ through locally advanced and, in certain cases, widespread metastatic disease. However, whether or not these models will more accurately predict drug activity against human cancer remains to be determined. Other alternatives, including three-dimensional tissue culture or xenografts of fresh human biopsy specimens onto immunocompromised mice, have the potential advantage of including the human microenvironment. However, these approaches have yet to prove their value relative to their cost.”, for example, page 253, Section “Predictive models”. Furthermore, Hait teaches that “It is now widely thought that biomarkers will drive a personalized approach to cancer drug development. The aim is that they will cut costs, decrease time to approval, and limit the number of patients who are exposed to potential toxicities without a reasonable chance of benefit — as exemplified by the development of imatinib and trastuzumab. However, recent attempts at repeating these successes in other cancer types have been less successful.”, for example, page 254, Section “Stratified/personalized medicine”. The challenges facing cancer drug development are further confirmed and discussed in Gravanis et al (Chin Clin Oncol, 2014, 3, pages 1 -5). Gravanis et al teach “The generic mechanism of action for cytotoxics made the prediction of which tumor types might respond to them very difficult, if not impossible, and necessitated a ‘trial and error’ approach against many different types of tumors.” and “The most prominent change in oncology drug development in the last 20 years has been the shift from classic cytotoxics to drugs that affect signaling pathways implicated in cancer, which belong to the so called ‘targeted therapies’.”, for example, page 1, Section “From cytotoxics to targeted therapies: how far are we from truly personalized medicine?”. Gravanis et al. further teach “Although constantly progressing, an understanding of cancer biology is far from complete. The ability to develop new compounds or generate biological data predictive of the clinical situation relies on good quality basic research data, although the complexity and constantly evolving biology of the tumor may be to blame for the frequent non-reproducibility of research results. Systemic biology approaches of the -omic type still generate largely incomprehensible, mostly due to their volume, analytical data, few pieces of which are currently actionable/drug-g-able. Finally, animal models of cancer are similarly unable to predict the clinical situation (for example, page 3, right column, the 2nd paragraph).
Beans (PNAS 2018; 115(50): 12539-12543) teaches that across cancer types, 90% of cancer deaths are caused not by the primary tumor but by metastasis. Beans teaches that although some drugs may shrink metastases along with primary tumors, no existing drugs treat or prevent metastasis directly (See page 12540). Beans states “Without a targeted approach, metastatic tumors often reemerge. “We shrink them, we send them back to their residual state, and they reenact those survival functions and retention of regenerative powers that made them metastasis-initiating cells in the first place” (See page 12540). Beans teaches that one of the major scientific challenges of studying metastatic disease is that different forms of cancer seem to metastasize through different mechanisms and the same form of cancer may metastasize differently in different subsets of patients (See page 12542). Of note, Beans states “It’s unlikely that one researcher is going to find one pathway that proves to be the key to metastasis” (See page 12542). Bean also teaches that translating many findings into therapies also presents unique hurdles in that it is difficult to measure the effectiveness of the therapy. Secondary tumors are often minuscule, and therefore, measuring success by tumor shrinkage may not work. Measuring the incidence of metastasis after treatment is also more difficult (See page 12542).
Given Bally et al teaching of treatment-limiting toxicities in clinical use; Sporn's teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype; Auerbach et al teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response; Gura's teaching that the models are unpredictable; Jain's teaching that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain; both Hait and Gravanis et al teaching various challenges facing cancer drug development, such as an understanding of cancer biology is far from complete, drug effects in preclinical cancer models often do not predict clinical results and many others; and Beans teachings that the field is highly underdeveloped with regards to preventing and treating cancer metastasis; the cited references demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers.
Taken together, the prior art ELP biopolymer drug carriers were able to induce apoptosis and inhibit proliferation of both dox-sensitive and resistant-cancer cells. However, the prior art does not teach any RGD-ELP and any anticancer agent can suppress drug resistance for all anticancer drugs of all tumor cells, and therefore, it is unclear if the claimed method would have the claimed function. Accordingly, one of skill in the art would conclude that the claimed invention encompasses a broad genus of suppressing drug resistance for all anticancer drugs of all tumor cells that may not respond to treatment with the claimed method. It should be noted that the specification has not demonstrated suppressing drug resistance for all anticancer drugs of all tumor cells with the claimed method. Based on the teaching of the instant specification and the prior art one of skill in the art would not conclude that Applicant was in possession of the claimed method of treating the genus of cancers.
Consequently, the method for suppressing drug resistance for all anticancer drugs of all tumor cells comprising administering an RGD-ELP and an anticancer agent, does not meet the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The applicant has not disclosed any species representative of the genus, which is highly variant. Applicant is reminded that Vas- Cath makes clear that the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is severable from its enablement provision. (See page 1115).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claim(s) 7-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huang, et al (referred as Huang from hereinafter) (Huang, K., Duan, N., Zhang, C. et al. Improved antitumor activity of TRAIL fusion protein via formation of self-assembling nanoparticle. Sci Rep 7, 41904 (2017). https://doi.org/10.1038/srep41904).
Although claim 1 is withdrawn from consideration as a non-elected claim, the limitations of claim 1 are referenced in order to examine claims 7 and 8. See objection of claim 1 above.
The instant claims are drawn to a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising extracellular matrix-anticancer drug conjugate comprising an extracellular matrix (RGD-ELP) and an anticancer agent connected by a linker, wherein the extracellular matrix comprises an elastin-like polypeptide and an integrin receptor ligand, and the extracellular matrix and the anticancer drug are connected to each other by a linker.
Huang, et al. teach RGD-TRAIL-ELP, which is a recombinant fusion protein comprising the RGD integrin receptor ligand that is genetically encoded within an elastin-like polypeptide, corresponding to the claimed RGD-containing elastin-like polypeptide (REP) (methods section). Huang further teach TRAIL as the anticancer agent which is an art-recognized therapeutic that selectively induces apoptosis in tumor cells (Results section). Huang further teaches a GGGGGG hexaglycine sequence that serves as a linker connecting the RGD-TRAIL to the ELP satisfying the linker limitation of claim 1 (figure 1)
Regarding instant claim 7, Huang discloses a method of treating in a subject comprising administering the conjugate encompassed by the limitation of claim 1. Huang et al teach intraperitoneal administration of RGD-0TRAIL-ELP to COLO-205 tumor bearing nude mice, resulting in significant inhibition of tumor growth and complete tumor regression at a dose of 8.25mg/mg/day (In vivo antitumor efficacy section), thereby disclosing a method of treating cancer in a subject by administering a pharmaceutical composition comprising the claimed conjugate.
Regarding instant claim 8, Huang teach treatment of colorectal cancer by the COLO-205 human colon carcinoma xenograft model (introduction, paragraph 4), which falls under one of the cancers recited in claim 8.
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.
9. Claims 7-11 are rejected under 35 U.S.C. 103 as being unpatentable over Huang, et al (referred as Huang from hereinafter) (Huang, K., Duan, N., Zhang, C. et al. Improved antitumor activity of TRAIL fusion protein via formation of self-assembling nanoparticle. Sci Rep 7, 41904 (2017). https://doi.org/10.1038/srep41904) in view of Bidwell, et al (referred as Bidwell from hereinafter) (Bidwell, G.L., Davis, A.N., Fokt, I. et al. A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance. Invest New Drugs 25, 313–326 (2007). https://doi.org/10.1007/s10637-007-9053-8)
Although claim 1 is withdrawn from consideration as a non-elected claim, the limitations of the claim are incorporated by reference into claims 7-11.
The instant claims are drawn to a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising extracellular matrix-anticancer drug conjugate comprising an extracellular matrix (RGD-ELP) and an anticancer agent connected by a linker, wherein the extracellular matrix comprises an elastin-like polypeptide and an integrin receptor ligand, and the extracellular matrix and the anticancer drug are connected to each other by a linker.
Huang, et al. teach RGD-TRAIL-ELP, which is a recombinant fusion protein comprising the RGD integrin receptor ligand that is genetically encoded within an elastin-like polypeptide, corresponding to the claimed RGD-containing elastin-like polypeptide (REP) (methods section). Huang further teach TRAIL as the anticancer agent which is an art-recognized therapeutic that selectively induces apoptosis in tumor cells (Results section). Huang further teaches a GGGGGG hexaglycine sequence that serves as a linker connecting the RGD-TRAIL to the ELP satisfying the linker limitation of claim 1 (figure 1). Regarding instant claim 7, Huang discloses a method of treating in a subject comprising administering the conjugate encompassed by the limitation of instant claim 1. Huang et al teach intraperitoneal administration of RGD-TRAIL-ELP to COLO-205 tumor bearing nude mice, resulting in significant inhibition of tumor growth and complete tumor regression at a dose of 8.25mg/mg/day (In vivo antitumor efficacy section), thereby disclosing a method of treating cancer in a subject by administering a pharmaceutical composition comprising the claimed conjugate. Regarding instant claim 8, Huang teach treatment of colorectal cancer by the COLO-205 human colon carcinoma xenograft model (introduction, paragraph 4), which falls under one of the cancers recited in instant claim 8.
Huang, et al. does not teach the suppression of anticancer drug resistance of tumor cells and increase apoptosis of tumor cells as recited in claims 9-11
However, Bidwell teaches that an ELP conjugated to doxorubicin (anticancer agent) overcomes the anticancer drug resistance of tumor cells. Bidwell further teaches that free doxorubicin was 67.6 times less effective in drug resistant MES-SA/Dx5 tumor cells compared to sensitive cells, while the ELP-doxorubicin conjugate was equally cytotoxic in both sensitive and resistant tumor cells (page 313, Table 1 at page 317). Bidwell further teaches that this result was confirmed in a second drug resistant cell line (NCI/ADR-RES, where free doxorubicin showed 31.9-fold resistance while the ELP conjugate showed essentially none (table 1, page 317). Bidwell teaches that this is due to the ELP conjugate bypassing the P-glycoprotein drug efflux pump that causes resistance (page 313). Bidwell further teaches that the ELP-doxorubicin conjugate induces apoptosis in drug resistant tumor cells via caspase activation (page 313 and 325).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to apply Bidwell’s ELP drug resistant resistance suppression and apoptosis inducing strategy which involves the conjugation of doxorubicin as an anticancer agent to Huang’s RGD-ELP conjugate. Huang, et al. teach that most TRAILS are rapidly excreted by the kidney, which results in a very short half-life and detracts the pharmaceutical application of TRAIL (discussion section). One of ordinary skill in the art could reasonably conclude the benefit of using doxorubicin that is taught by Bidwell, instead of TRAIL is that doxorubicin is not rapidly excreted by the kidneys and also demonstrated that the use of doxorubicin delivery using an ELP-based polypeptide vector can overcome the P-glycoprotein mediated drug resistance allowing for induced apoptosis and inhibit proliferation of multidrug-resistant tumor cells (discussion section). One of ordinary skill in the art would have recognized combining Huang’s RGD-mediated tumor targeting with Bidwell’s ability to overcome drug resistance and increase apoptosis with the conjugation of doxorubicin would yield a therapeutically optimal conjugate with a reasonable expectation of success given the structural compatibility of the teachings from both Huang and Bidwell. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, B.).
10. Claims 7-11 are rejected under 35 U.S.C. 103 as being unpatentable over Huang, et al (referred as Huang from hereinafter) (Huang, K., Duan, N., Zhang, C. et al. Improved antitumor activity of TRAIL fusion protein via formation of self-assembling nanoparticle. Sci Rep 7, 41904 (2017). https://doi.org/10.1038/srep41904) in view of Raucher, et al. (WO 2007/090094 A2, published 9 August 2007).
Although claim 1 is withdrawn from consideration as a non-elected claim, the limitations of the claim are incorporated by reference into claims 7-11.
The instant claims are drawn to a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising extracellular matrix-anticancer drug conjugate comprising an extracellular matrix (RGD-ELP) and an anticancer agent connected by a linker, wherein the extracellular matrix comprises an elastin-like polypeptide and an integrin receptor ligand, and the extracellular matrix and the anticancer drug are connected to each other by a linker.
Huang, et al. teach RGD-TRAIL-ELP, which is a recombinant fusion protein comprising the RGD integrin receptor ligand that is genetically encoded within an elastin-like polypeptide, corresponding to the claimed RGD-containing elastin-like polypeptide (REP) (methods section). Huang further teach TRAIL as the anticancer agent which is an art-recognized therapeutic that selectively induces apoptosis in tumor cells (Results section). Huang further teaches a GGGGGG hexaglycine sequence that serves as a linker connecting the RGD-TRAIL to the ELP satisfying the linker limitation of claim 1 (figure 1). Regarding instant claim 7, Huang discloses a method of treating in a subject comprising administering the conjugate encompassed by the limitation of instant claim 1. Huang et al teach intraperitoneal administration of RGD-TRAIL-ELP to COLO-205 tumor bearing nude mice, resulting in significant inhibition of tumor growth and complete tumor regression at a dose of 8.25mg/mg/day (In vivo antitumor efficacy section), thereby disclosing a method of treating cancer in a subject by administering a pharmaceutical composition comprising the claimed conjugate. Regarding instant claim 8, Huang teach treatment of colorectal cancer by the COLO-205 human colon carcinoma xenograft model (introduction, paragraph 4), which falls under one of the cancers recited in instant claim 8.
Huang, et al. does not teach the suppression of anticancer drug resistance of tumor cells and increase apoptosis of tumor cells as recited in claims 9-11
However, Raucher, et al. teach the ELP -based doxorubicin carrier is capable of circumventing the most common pathway of drug resistance, a drug pumping mechanism that allows tumor cells to remove small molecule drugs and continue to survive in the presence of these drugs. Raucher, et al. demonstrates that ELP-delivered doxorubicin may be used to overcome drug resistance of tumor cells (paragraph 48). Raucher, et al. further teach the ELP-delivered Dox induced apoptosis (paragraph 15).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to apply Raucher’s ELP drug resistant suppression and apoptosis inducing strategy which involves the conjugation of doxorubicin as an anticancer agent to Huang’s RGD-ELP conjugate. Huang, et al. teach that most TRAILS are rapidly excreted by the kidney, which results in a very short half-life and detracts the pharmaceutical application of TRAIL (discussion section). One of ordinary skill in the art could reasonably conclude the benefit of using doxorubicin that is taught by Raucher, instead of TRAIL is that doxorubicin is not rapidly excreted by the kidneys and also demonstrated that the use of doxorubicin delivery using an ELP-based polypeptide vector can overcome the P-glycoprotein mediated drug resistance allowing for induced apoptosis and inhibit proliferation of multidrug-resistant tumor cells (discussion section). One of ordinary skill in the art would have recognized combining Huang’s RGD-mediated tumor targeting with Raucher’s ability to overcome drug resistance and increase apoptosis with the conjugation of doxorubicin would yield a therapeutically optimal conjugate with a reasonable expectation of success given the structural compatibility of the teachings from both Huang and Bidwell. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, B.).
Conclusion
11. No claims are allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Syed J Abbas whose telephone number is (571)272-0015. The examiner can normally be reached M-Th, 9:00AM-4:00PM.
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/SYED J ABBAS/Examiner, Art Unit 1674
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