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 of species without traverse of invention the chemotherapeutic agent of gemcitabine for group I, encompassing claims 1-25, the immune checkpoint inhibitor of Nivolumab for group II, encompassing claims 1-25, a small molecule targeting drug of sorafenib for group III, encompassing claims 1-25, and a tumor-associated antigen-specific antibody of Herceptin for group IV, encompassing claims 1- 25) in the reply filed on 2/25/2026 is acknowledged.
3. Species election was made without traverse in the reply filed on 1/13/2026. The amendments filed 2/25/2026 are acknowledged. Claim 25 is amended. Claims 1-25 are pending and under examination.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted 13 July 2023 and the references cited therein have been considered, unless indicated otherwise.
Objection to the Specification
5. The use of the terms P1101, Pegberon, Pegasys, Pegintron, Infergen, Novaferon, INTRONA, Roferon-A, PEGINFER and Herceptin, which are a trade name or a mark used in commerce, has been noted in this application. The term 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 term.
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 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 regarding using “mutants and derivative thereof” language.
5. First, claims 1-18 and 20-25 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 1 is drawn to a method for treating cancer in a subject, comprising administering an interferon-based therapeutic agent and administering an additional anti-cancer agent.
The claims and specification teaches that the interferon-based therapeutic agent in combination with an additional anti-cancer agent is useful in treatment for a variety of cancers (See page 4). The specification teaches that cancer can include: leukemia (such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia, polycapillary leukemia, liver cancer, lung cancer, colorectal cancer, skin cancer, stomach cancer, breast cancer, prostate cancer, non-Hodgkin's lymphoma, melanoma, multiple myeloma, laryngeal papilloma, follicular lymphoma, AIDS-related Kaposi's sarcoma and renal cell carcinoma, preferably liver cancer, lung cancer, breast cancer, colorectal cancer or melanoma (See page 4). The specification provides working examples of interferon combined with an anticancer agent to treat liver cancer, colorectal cancer and breast cancer.
A method for treating cancer in a subject, comprising i) intermittently administering an interferon-based therapeutic agent for a plurality of consecutive treatment courses; and ii) administering an additional anticancer agent, to the subject 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 that interferons bind to the same receptors which are widely distributors in for example monocyte-macrophages, polymorphonuclear leukocytes, B cells, T cells, platelets, epithelial cells, endothelial and tumor cells; however, this is not deemed to be predicative of treating all cancers using the claimed method. The claims broadly encompass the use of interferon in combination with an anticancer agent to treat all cancers; however, the specification does not demonstrate that the antibody 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. 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 interferon-B with cisplatin on human breast adenocarcinoma is discussed by Ethiraj et al. (Synergistic anti-carcinogenic effect of interferon-β with cisplatin on human breast adenocarcinoma MDA MB231 cells, International Immunopharmacology, Volume 23, Issue 1, 2014, Pages 222-228, ISSN 1567-5769, https://doi.org/10.1016/j.intimp.2014.08.010). Ethiraj et al. disclose the combination of interferon β with reduced dose of cisplatin results synergistically improved growth-inhibition and apoptosis-inducing effect on MDA MB231 cell. The state of the art regarding the use of interferon-a and an anticancer agent to treat human hepatocellular carcinoma cells is discussed by Wada et al. (Combination therapy of interferon-alpha and 5-fluorouracil inhibits tumor angiogenesis in human hepatocellular carcinoma cells by regulating vascular endothelial growth factor and angiopoietins. Oncol Rep. 2007 Oct;18(4):801-9. PMID: 17786339.). Wada et al. teach that IFN-alpha and 5-FU combination therapy has anti-proliferative and anti-angiogenic effects and can induce apoptosis in vivo.
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 interferon and 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 rumors 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 recognizes that interferon-a and -b, and 5-fluorouracil and cisplatin can treat hepatocellular carcinoma and adenocarcinoma. However, the prior art does not teach any interferon based therapeutic agent 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 interferon=based therapeutic agent 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 2, 4 and 5 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The 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 instant claims are drawn to the method according to claim 1, wherein the interferon-based therapeutic agent comprises an interferon or a mutant or derivative thereof, or comprises a nucleic acid molecule encoding an interferon or a mutant or a derivative thereof, or comprises a substance promoting the generation of an endogenous interferon; wherein the interferon- based therapeutic agent comprises interferon a 2a, interferon a 2b, interferon a 1n, interferon lambda, or a mutant or derivative thereof; wherein the interferon or the mutant or derivative thereof is PEGylated.
The specification teaches that interferon mutants and interferon derivatives have been approved to be widely used in various treatments. Interferons and mutants that have been approved for human clinical treatment include interferon a 2a, interferon a 2b, interferon a 1b, compound interferon (Infergen), and interferon mutants (such as Novaferon), Interferon b, interferon lambda, Peginterferon a 2a, Peginterferon a 2b, integrated interferon and the like.
The issue with regard to the written description provision is that the genus of different forms of interferon is not adequately described. Although the claims are inclusive of the multiple interferon families, the claims also broadly encompass interferon mutants or derivatives thereof. The specification provides no guidance regarding which amino acids can be modified in the mutants or derivatives thereof, while maintaining any given function. Therefore, these structures (i.e., different forms) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences).
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between the claimed interferon families, and the claimed functions, this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed interferons (Type I, Type II or Type III interferon, such as interferon a, interferon b, interferon y or interferon lambda, preferably interferon a, interferon a 2a, interferon a 2b, interferon a 1b, interferon lambda and etc.) and encompass different forms of interferon that are mutants and derivatives thereof. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only one species has been described and this is not considered to be representative of the breadth of the genus. Therefore, given the lack of structure function correlation and the lack of a representative number of species, the specification provides insufficient written description to support the genus encompassed by the claim.
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.)
With the exception of the specific interferon provided in the claims and specification, the skilled artisan cannot envision the detailed chemical structure of the encompassed combination therapies, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
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.
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in surviving results in the conversion of surviving’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al., Burgess et al., and Defeo-Jones et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted based on sequence identity. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the proteins per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The 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 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
7. Claims 6 and 25 contain the trademark/trade names P1101, Pegberon, Pegasys, Pegintron, Infergen, Novaferon, INTRONA, Roferon-A, PEGINFER and Herceptin. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe interferon based therapeutic agents and a tumor associated antigen specific antibody (Herceptin) and, accordingly, the identification/description is indefinite.
8. The term “substantially” in claims 9, 17 and 18 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The word at least introduces a range of possibilities and even wider in some interpretations which causes ambiguity. The rationale for avoiding such phrasing comes down to accuracy, reproducibility and the proper representation of uncertainty.
Claim Rejections - 35 USC § 102
(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.
9. Claim(s) 1, 2, 3, 4 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Escudier, et al. (Phase III Trial of Bevacizumab Plus Interferon Alfa-2a in Patients With Metastatic Renal Cell Carcinoma (AVOREN): Final Analysis of Overall Survival. J Clin Oncol 28, 2144-2150(2010). DOI:10.1200/JCO.2009.26.7849).
The instant claims are drawn to a method for treating cancer in a subject comprising administering an interferon based therapeutic agent for a plurality of consecutive treatment courses and administering an additional anticancer agent to the subject.
Escudier, et al. teach a phase III trial of bevacizumab, which is an anticancer agent, in combination with interferon alpha-2a, to treat metastatic renal cell carcinoma, that was administered every 2 weeks until disease progression, unacceptable toxicity, or withdrawal of consent, which indicates administration was in consecutive treatment courses (procedure section). Thus, Escudier, et al. anticipates instant claim 1 as Escudier highlights the combination of both the interferon and anticancer agent used to treat a specific cancer in a specific treatment courses that occurred consecutively.
Escudier, et al. teach that the interferon-based therapeutic agent was that was used was interferon alpha-2a, which anticipates the limitation of instant claim 2 that required the interferon-based therapeutic agent to comprise an interferon (introduction section, paragraph 1).
Escudier, et al. teach interferon alpha-2a was used in the phase III trial. Instant claim 3 the interferon to multiple variants including interferon alpha, which is the genus of the interferon alpha-2a, and instant claim 4 limits the interferon to interferon alpha-2a (introduction section, paragraph 1 and 2). As such, Escudier anticipates both the genus of interferon alpha in instant claim 3 and anticipates instant claim 4 as both Escudier and the instant claim 4 teach the same interferon.
Escudier, et al. teach the interferon and anticancer agent is used in combination to treat metastatic renal cell carcinoma (introduction section, paragraph 1). Instant claim 19 teach the method according to claim 1, where in the selected from various cancers, including renal cell carcinoma which is the same cancer taught by Escudier.
10. Claims 1-4, 6, 11-14, 16-19, 20, 22-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dutcher, et al. (Janice P. Dutcher, Theodore Logan, Michael Gordon, Jeffrey Sosman, Geoffrey Weiss, Kim Margolin, Terry Plasse, James Mier, Michael Lotze, Joseph Clark, Michael Atkins; Phase II Trial of Interleukin 2, Interferon α, and 5-Fluorouracil in Metastatic Renal Cell Cancer: A Cytokine Working Group Study1. Clin Cancer Res 1 September 2000; 6 (9): 3442–3450.)
The instant claims are drawn to a method for treating cancer in a subject comprising administering an interferon based therapeutic agent for a plurality of consecutive treatment courses and administering an additional anticancer agent to the subject.
Dutcher, et al. teach a method of treating metastatic renal cell cancer in patients, comprising administering an interferon based therapeutic agent, specifically, interferon a 2b (Intron-A) and an anticancer agent, specifically 5-fluoroucil (5FU) over 8 consecutive weeks. Instant claims 1, 2, 3, 4, 6 teach method for treating cancer in a subject administering interferon-based therapeutic agent and additional anticancer agent; said interferon agent can be an interferon (instant claim 2), said interferon can be interferon-a (instant claim 3), said interferon-a can be interferon-a 2b (instant claim 4), and said interferon-based therapeutic agent can be Intron-A (instant claim 6), and wherein the cancer is renal cell carcinoma. Thus, Dutcher, et al. anticipate the invention taught in instant claims 1, 2, 3, 4, 6 and 19.
Dutcher, et al. teach the interferon a-2b was administered on day 1 of weeks 1 through 4, day 1 of weeks 3 through 5 and three times weekly during week 5 through 8. 5FU was administered once weekly during weeks 5 through 8. Indicated by table 1 below, treatment for each plurality of consecutive treatment lasted 8 weeks, and Dutcher, et al. teach the intervals between the consecutive treatment courses and the duration of the consecutive treatment courses are substantially the same as Dutcher, et al. show in the treatment plan section, each cycle would last 8 weeks and there would be a 2-4 weeks rest after each cycle. As such, the duration and cycles taught by Dutcher, et al. anticipate by the durations taught in instant claims 11-14 and 16-18.
PNG
media_image1.png
691
664
media_image1.png
Greyscale
Based on the table above, Dutcher, et al. teach that the interferon-based therapeutic agent does not overlap with the administration of the additional anticancer agent in weeks 1-4, and the interferon-based therapeutic agent does overlap with the administration of the additional anticancer agent in weeks 5-8. The anticancer agent is administered during and between plurality of consecutive treatment courses when the interferon and anticancer overall. Dutcher, et al. teach the administration of the anticancer agent according to its conventional scheme in table 1. Table 1 demonstrates the administration of the anticancer agent according to its convention and thus, meets the limitation of instant claim 24. Thus, instant claims 20, 22-24 are anticipated by Dutcher, et al.
11. Claim(s) 1-6, 11-18, 20-21 and 24-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dijkgraaf, et al. (A phase 1/2 study combining gemcitabine, Pegintron and p53 SLP vaccine in patients with platinum-resistant ovarian cancer. Oncotarget. 2015 Oct 13;6(31):32228-43. doi: 10.18632/oncotarget.4772. PMID: 26334096; PMCID: PMC4741673.)
The instant claims are drawn to a method for treating cancer in a subject comprising administering an interferon based therapeutic agent for a plurality of consecutive treatment courses and administering an additional anticancer agent to the subject.
Dijkgraaf, et al. teach a phase 1/2 trial in which patients received a combination of Pegintron, which is a PEGylated interferon-based therapeutic agent, specifically interferon a-2b, and gemcitabine, which is an anticancer agent, to treat cancer, specifically platinum-resistant ovarian cancer (experimental design paragraph). Instant claims 1, 2, 3, 4, 5, 6 and 25 teach method for treating cancer in a subject administering interferon-based therapeutic agent and additional anticancer agent; said interferon agent can be an interferon (instant claim 2), said interferon can be interferon-a (instant claim 3), said interferon-a can be interferon-a 2b (instant claim 4), said interferon can be PEGylated (instant claim 4), said interferon-based therapeutic agent can be Pegintron (instant claim 6) and said anticancer agent can be gemcitabine. Thus, Dijkgraaf, et al. anticipate the invention taught in instant claims 1, 2, 3, 4, 5, 6 and 25. Dijkgraaf, et al. also teach in colorectal cancer patients the combination of this p53 SLP vaccine with IFN-α on the injection site resulted in enhanced inflammation as well as stronger and better type 1 cytokine polarized p53-specific CD4+ and CD8+ T-cell responses. P53 SLP vaccine is an anti-cancer agent as well (paragraph 3).
Dijkgraaf, et al. teach patients received 6 cycles of gemcitabine 1000 and IFN-α 2b, 7 days prior and 22 days after to the first infusion of gemcitabine. In other words, the 6 cycles represent a “plurality of consecutive treatment courses” as taught by the applicant, and each cycle lasts 3 weeks, with 1 week off that repeats for a total of 6 cycles. Dijkgraaf, et al. teach a single cycle of Gemcitabine usually lasts 3-4 weeks (weekly for 3 weeks, then 1 week off) (treatment schedule paragraph). Therefore, a course consisting of 1 to 6 cycles, with an interval of 3 weeks of treatment coincided with 1 week off fit well within the duration mentioned in instant claims 11, 12, 13, 14, 15, and 16.
Dijkgraaf, et al. teach that Cycle 1, Cycle 2, ..., Cycle 6 all follow this exact same timing, with the same intervals repeated during the 6 cycles (treatment schedule section), making the treatment "substantially the same" in duration across all six iterations, as recited in instant claim 17 and 18.
Dijkgraaf, et al. teach IFN is given 7 days before, then stops. Gemcitabine is administered in 6 cycles (often days 1, 8, 15 of a 28-day cycle)(treatment schedule section). The interferon is resumed 22 days after the initial chemotherapy start date but does not overlap with Gemcitabine administration. This meets the limitation taught by instant claim 20.
Dijkgraaf teach that interferon is given 7 days prior to start of the anticancer treatment, and on the 22nd day, after 3 weeks of gemcitabine (treatment schedule section). Instant claim 21 recites the additional anticancer agent is administered between the plurality of consecutive treatment courses, which is taught by Dijkgraaf. This meets the limitation of instant claim 21.
Dijkgraaf teach the administration of the anticancer agent according to its conventional scheme in table 1. Table 1 demonstrates the administration of the anticancer agent according to its convention and thus, meets the limitation of instant claim 24.
PNG
media_image2.png
519
787
media_image2.png
Greyscale
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.
12. Claim(s) 1-8, 11-18, 20-21 and 24-25 are rejected under 35 35 U.S.C. 103 as being anticipated by Dijkgraaf, et al. (A phase 1/2 study combining gemcitabine, Pegintron and p53 SLP vaccine in patients with platinum-resistant ovarian cancer. Oncotarget. 2015 Oct 13;6(31):32228-43. doi: 10.18632/oncotarget.4772. PMID: 26334096; PMCID: PMC4741673.) in view of Argonne (A new molecule could help put the sting on cancer | advanced photon source. Argonne National Laboratory. (2019, March 13). https://www.aps.anl.gov/APS-Science-Highlight/2019-03-13/a-new-molecule-could-help-put-the-sting-on-cancer).
The instant claims are drawn to a method for treating cancer in a subject comprising administering an interferon based therapeutic agent for a plurality of consecutive treatment courses and administering an additional anticancer agent to the subject.
Dijkgraaf, et al. teach a phase 1/2 trial in which patients received a combination of Pegintron, which is a PEGylated interferon-based therapeutic agent, specifically interferon a-2b, and gemcitabine, which is an anticancer agent, to treat cancer, specifically platinum-resistant ovarian cancer (experimental design paragraph). Instant claims 1, 2, 3, 4, 5, 6 and 25 teach method for treating cancer in a subject administering interferon-based therapeutic agent and additional anticancer agent; said interferon agent can be an interferon (instant claim 2), said interferon can be interferon-a (instant claim 3), said interferon-a can be interferon-a 2b (instant claim 4), said interferon can be PEGylated (instant claim 4), said interferon-based therapeutic agent can be Pegintron (instant claim 6) and said anticancer agent can be gemcitabine. Thus, Dijkgraaf, et al. anticipate the invention taught in instant claims 1, 2, 3, 4, 5, 6 and 25. Dijkgraaf, et al. also teach in colorectal cancer patients the combination of this p53 SLP vaccine with IFN-α on the injection site resulted in enhanced inflammation as well as stronger and better type 1 cytokine polarized p53-specific CD4+ and CD8+ T-cell responses. P53 SLP vaccine is an anti-cancer agent as well (paragraph 3). Dijkgraaf, et al. teach patients received 6 cycles of gemcitabine 1000 and IFN-α 2b, 7 days prior and 22 days after to the first infusion of gemcitabine. In other words, the 6 cycles represent a “plurality of consecutive treatment courses” as taught by the applicant, and each cycle lasts 3 weeks, with 1 week off that repeats for a total of 6 cycles. Dijkgraaf, et al. teach a single cycle of Gemcitabine usually lasts 3-4 weeks (weekly for 3 weeks, then 1 week off) (treatment schedule paragraph). Therefore, a course consisting of 1 to 6 cycles, with an interval of 3 weeks of treatment coincided with 1 week off fit well within the duration mentioned in instant claims 11, 12, 13, 14, 15, and 16. Dijkgraaf, et al. teach that Cycle 1, Cycle 2, ..., Cycle 6 all follow this exact same timing, with the same intervals repeated during the 6 cycles (treatment schedule section), making the treatment "substantially the same" in duration across all six iterations, as recited in instant claim 17 and 18. Dijkgraaf, et al. teach IFN is given 7 days before, then stops. Gemcitabine is administered in 6 cycles (often days 1, 8, 15 of a 28-day cycle)(treatment schedule section). The interferon is resumed 22 days after the initial chemotherapy start date but does not overlap with Gemcitabine administration. This meets the limitation taught by instant claim 20. Dijkgraaf teach that interferon is given 7 days prior to start of the anticancer treatment, and on the 22nd day, after 3 weeks of gemcitabine (treatment schedule section). Instant claim 21 recites the additional anticancer agent is administered between the plurality of consecutive treatment courses, which is taught by Dijkgraaf. This meets the limitation of instant claim 21. Dijkgraaf teach the administration of the anticancer agent according to its conventional scheme in table 1. Table 1 demonstrates the administration of the anticancer agent according to its convention and thus, meets the limitation of instant claim 24.
Dijkgraaf, et al. does not teach an interferon-based therapeutic such as an interferon agonist that activates the STINGs signaling pathway such as di (instant claim 7) and does not teach the specific cancers such as colorectal cancer (instant claim 19).
However, Argonne teach that immunomodulatory approaches using agonists to target STING signaling are therefore being investigated as anticancer treatments such as amidobenzimidazole (ABZI). Argonne further teach researchers produced a diABZI compound by covalently linking together two of the ABZI compounds. They found that the diABZI bound to STING ~1000-fold more tightly than the original ABZI did. Argonne, et al also teach that diABZI was also tested in mouse models of colorectal cancer. It was found that the diABZI-treated mice showed improved survival and tumor regression, with eight out of ten mice being tumor-free by day 43. Dijkgraaf, et al. teach an interferon-based therapeutic agent (Pegintron (interferon a 2b)) and an anticancer agent to treat cancer in general but also mention the benefit in subjects with colorectal cancer. Argonne teach an interferon-based therapeutic agent, diABZI, is beneficial to treat cancer in general, but specify that the treatment was successful in mouse models with colorectal cancer. One of ordinary skill in the art could reasonably incorporate the teaching of Dijkgraaf, et al. by replacing the interferon-based therapeutic agent from interferon-a 2b to using diABZI taught by Argonne in combination with the gemcitabine anticancer agent taught by Dijkgraaf to treat colorectal cancer in a subject. 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.).
13. Claim(s) 1-6, 9, 11-18, 20-21 and 24-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dijkgraaf, et al. (A phase 1/2 study combining gemcitabine, Pegintron and p53 SLP vaccine in patients with platinum-resistant ovarian cancer. Oncotarget. 2015 Oct 13;6(31):32228-43. doi: 10.18632/oncotarget.4772. PMID: 26334096; PMCID: PMC4741673.) in view of Ozcimen, et al. (Ozcimen, S., Bitirgen, M., & Kandemir, B. (2015). Role of Neopterin in Determining the Efficacy of Interferon Therapy in Chronic Hepatitis B and C. European Journal of General Medicine, 12(1), 1-6. https://doi.org/10.15197/sabad.1.12.01)
The instant claims are drawn to a method for treating cancer in a subject comprising administering an interferon based therapeutic agent for a plurality of consecutive treatment courses and administering an additional anticancer agent to the subject.
Dijkgraaf, et al. teach a phase 1/2 trial in which patients received a combination of Pegintron, which is a PEGylated interferon-based therapeutic agent, specifically interferon a-2b, and gemcitabine, which is an anticancer agent, to treat cancer, specifically platinum-resistant ovarian cancer (experimental design paragraph). Instant claims 1, 2, 3, 4, 5, 6 and 25 teach method for treating cancer in a subject administering interferon-based therapeutic agent and additional anticancer agent; said interferon agent can be an interferon (instant claim 2), said interferon can be interferon-a (instant claim 3), said interferon-a can be interferon-a 2b (instant claim 4), said interferon can be PEGylated (instant claim 4), said interferon-based therapeutic agent can be Pegintron (instant claim 6) and said anticancer agent can be gemcitabine. Thus, Dijkgraaf, et al. anticipate the invention taught in instant claims 1, 2, 3, 4, 5, 6 and 25. Dijkgraaf, et al. also teach in colorectal cancer patients the combination of this p53 SLP vaccine with IFN-α on the injection site resulted in enhanced inflammation as well as stronger and better type 1 cytokine polarized p53-specific CD4+ and CD8+ T-cell responses. P53 SLP vaccine is an anti-cancer agent as well (paragraph 3).
Dijkgraaf, et al. teach patients received 6 cycles of gemcitabine 1000 and IFN-α 2b, 7 days prior and 22 days after to the first infusion of gemcitabine. In other words, the 6 cycles represent a “plurality of consecutive treatment courses” as taught by the applicant, and each cycle lasts 3 weeks, with 1 week off that repeats for a total of 6 cycles. Dijkgraaf, et al. teach a single cycle of Gemcitabine usually lasts 3-4 weeks (weekly for 3 weeks, then 1 week off) (treatment schedule paragraph). Therefore, a course consisting of 1 to 6 cycles, with an interval of 3 weeks of treatment coincided with 1 week off fit well within the duration mentioned in instant claims 11, 12, 13, 14, 15, and 16.
Dijkgraaf, et al. teach that Cycle 1, Cycle 2, ..., Cycle 6 all follow this exact same timing, with the same intervals repeated during the 6 cycles (treatment schedule section), making the treatment "substantially the same" in duration across all six iterations, as recited in instant claim 17 and 18.
Dijkgraaf, et al. teach IFN is given 7 days before, then stops. Gemcitabine is administered in 6 cycles (often days 1, 8, 15 of a 28-day cycle)(treatment schedule section). The interferon is resumed 22 days after the initial chemotherapy start date but does not overlap with Gemcitabine administration. This meets the limitation taught by instant claim 20.
Dijkgraaf teach that interferon is given 7 days prior to start of the anticancer treatment, and on the 22nd day, after 3 weeks of gemcitabine (treatment schedule section). Instant claim 21 recites the additional anticancer agent is administered between the plurality of consecutive treatment courses, which is taught by Dijkgraaf. This meets the limitation of instant claim 21.
Dijkgraaf teach the administration of the anticancer agent according to its conventional scheme in table 1. Table 1 demonstrates the administration of the anticancer agent according to its convention and thus, meets the limitation of instant claim 24.
Dijkgraaf does not teach the interferon-based therapeutic agent is administered such that during substantially the entire course, the concentration of neopterin in the subject is higher than the concentration of neopterin before the first administration, for example approximately 110%, approximately 120%, approximately 130%, approximately 140%, approximately 150%, approximately 200%, approximately 250% or higher of the neopterin concentration before the first administration (instant claim 9)
However, Ozcimen, et al. teach neopterin concentration is higher in a subject that the concentration of neopterin before the first administration. Ozcimen, et al. teach in the study made by Oxenkrug, et al. on 260 patients who received peginterferon alpha therapy, they observed that the rate at which the patients responded to the treatment was correlated with neopterin concentrations. They found that before the antiviral treatment the response to treatment rates of the patients whose serum neopterin levels were ≤16 nmol/L were higher than those of the patients whose serum neopterin levels were ≥16 nmol/L. Ozcimen, et al. teach that in most treatment, a decrease is seen in neopterin levels because of the decline in immune system activation at the end of treatment. Ozcimen, et al. teach that neopterin can be used in determining the efficacy of interferon. This shows that obtain concentration of neopterin prior to and after therapy is routine. Thus, one of ordinary skill in the art, prior to administering the interferon-based therapeutic agent and anticancer agent taught by Dijkgraaf, can incorporate the teachings of Ozcimen, et al., by taking the concentration levels of neopterin of a patient before therapy. A rationale to support a conclusion that a 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 would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
Double Patenting
14. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
15. Claims 1-19, 21 and 23 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 16, 17, 18, 19, 20, 21, 22, 23 of copending Application No. 18273323 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 recites a method for treating cancer in a subject, comprising i) intermittently administering an interferon-based therapeutic agent for a plurality of consecutive treatment courses; and ii) administering an additional anticancer agent, to the subject. Claim 1 of Copending application ‘323 recites a method for treating cancer in a subject, comprising i) intermittently administering an interferon-based therapeutic agent for a plurality of consecutive treatment courses; and ii) administering an additional anticancer agent, to the subject, wherein the additional anticancer agent is administered after the first administration of the interferon-based therapeutic agent in the plurality of consecutive treatment courses. The copending application anticipates instant claim 1.
Instant claim 2 recites wherein the interferon-based therapeutic agent comprises an interferon or a mutant or derivative thereof, or comprises a nucleic acid molecule encoding an interferon or a mutant or a derivative thereof, or comprises a substance promoting the generation of an endogenous interferon. Claim 16 of copending application ‘323 recites the method according to claim 1, the interferon-based therapeutic agent comprises an interferon or a mutant or derivative thereof, or comprises a nucleic acid molecule encoding an interferon or a mutant or a derivative thereof, or comprises a substance promoting the generation of an endogenous interferon. The copending application anticipates instant claim 2.
Instant claim 3 recites wherein the interferon is a Type I, Type II or Type III interferon, such as interferon a, interferon b, interferon gamma or interferon lambda, preferably interferon a. Claim 17 of copending application ‘323 recites the method according to claim 1, the interferon is a Type I, Type II or Type III interferon, such as interferon a, interferon b, interferon gamma or interferon lambda, preferably. The copending application anticipates instant claim 3.
Instant claim 4 recites wherein the interferon-based therapeutic agent comprises a 2a, interferon a 2b, interferon a 1b, interferon lambda, or a mutant or derivative thereof. Claim 18 of copending application ‘323 recites the interferon the interferon-based therapeutic agent comprises a 2a, interferon a 2b, interferon a 1b, interferon lambda, or a mutant or derivative thereof. The copending application anticipates instant claim 4,
Instant claim 5 recites wherein the interferon or the mutant or derivative thereof is PEGylated. Claim 19 of copending application ‘323 recites the interferon or the mutant or derivative thereof is PEGylated. The copending application anticipates instant claim 5.
Instant claim 6 recites wherein the interferon- based therapeutic agent is selected from the group consisting of P1101, Pegberon, Pegasys,Pegintron, Infergen, Novaferon, INTRONA, Roferon-A, Hapgen, PEGINFER and Peginterferon. Claim 20 of copending application ‘323 recites the interferon-based therapeutic agent is selected from the group consisting of P1101, Pegberon, Pegasys, Pegintron, Infergen, Novaferon, INTRONA, Roferon-A, Hapgen, PEGINFER and Peginterferon. The copending application anticipates instant claim 6.
Instant claim 7 recites wherein the interferon- based therapeutic agent comprises an agonist of the TLRs, RLRs, and STINGs signaling pathways. Claim 21 of copending application ‘323 recites the interferon-based therapeutic agent comprises an agonist of the TLRs, RLRs, and STINGs signaling pathways. The copending application anticipates instant claim 7.
Instant claim 8 recites wherein the interferon-based therapeutic agent is selected from the group consisting of GS-9620, GS-9688, R07020531,R06864018, TQ-A3334, JNJ-4964, SB9200, MIW815, DMXAA, MK-1454, and diABZI. Claim 22 of copending application recites the interferon-based therapeutic agent is selected from the group consisting of GS-9620, GS-9688, R07020531, R06864018, TQ-A3334, JNJ-4964, SB9200, MIW815, DMXAA, MK-1454, and diABZ. The copending application anticipates instant claim 8.
Instant claim 9 recites wherein in the consecutive treatment course, the interferon-based therapeutic agent is administered such that during substantially the entire course, the concentration of neopterin in the subject is higher than the concentration of neopterin before the first administration, for example approximately 110%, approximately 120%, approximately 130%, approximately 140%, approximately 150%, approximately 200%, approximately 250% or higher of the neopterin concentration before the first administration. Claim 3 of copending application ‘323 recites wherein in the consecutive treatment course, the interferon-based therapeutic agent is administered such that during substantially the entire course, the concentration of neopterin in the subject is higher than the concentration of neopterin before the first administration in said treatment course, for example approximately 110%, approximately 120%, approximately 130%, approximately 140%, approximately 150%, approximately 200%, approximately 250% or higher of the neopterin concentration before the first administration. The copending application anticipates instant claim 9.
Instant claim 10 recites wherein the duration of the consecutive treatment course is the time period from the first administration to the last administration, plus about 5 in vivo half-lives of the therapeutic agent. Claim 4 of copending application ‘323 recites the duration of the consecutive treatment course is the time period from the first administration of the interferon-based therapeutic agent to the last administration, plus about 5 in vivo half-lives of the interferon-based therapeutic agent. The copending application anticipates instant claim 10.
Instant claim 11 recites wherein the duration of each of the plurality of consecutive treatment courses is from about 1 week to about 24 weeks, preferably from about 1 week to about 12 weeks, further preferably from about 1 week to about 8 weeks, and yet further preferably about 2 weeks to about 6 weeks. Claim 5 of copending application ‘323 recites the duration of each of the plurality of consecutive treatment courses is from about 1 week to about 24 weeks, preferably from about 1 week to about 12 weeks, further preferably from about 1 week to about 8 weeks, and yet further preferably about 2 weeks to about 6 weeks. The copending application anticipates instant claim 11.
Instant claim 12 recites wherein the duration of each of the consecutive treatment courses is about 1 week to about 12 weeks, and the interval between the consecutive treatment courses is about 1 week to about 12 weeks. Claim 6 of copending application ‘323 recites the duration of each of the consecutive treatment courses is about 1 week to about 12 weeks, and the interval between the consecutive treatment courses is about 1 week to about 12 weeks. The copending application anticipates instant claim 12.
Instant claim 13 recites wherein the interval between the consecutive treatment courses is from about 1 week to about 24 weeks, preferably from about 1 week to about 12 weeks, further preferably from about 1 week to about 8 weeks, and yet further preferably about 2 weeks to about 6 weeks. Claim 7 of copending application ‘323 recites the interval between the consecutive treatment courses is from about 1 week to about 24 weeks, preferably from about 1 week to about 12 weeks, further preferably from about 1 week to about 8 weeks, and yet further preferably about 2 weeks to about 6 weeks. The copending application anticipates instant claim 13.
Instant claim 14 recites wherein the duration of each of the consecutive treatment courses is about 1 week to about 8 weeks, and the interval between the consecutive treatment courses is about 1 week to about 8 weeks. Claim 8 of copending application ‘323 recites the duration of each of the consecutive treatment courses is about 1 week to about 8 weeks, and the interval between the consecutive treatment courses is about 1 week to about 8 weeks. The copending application anticipates instant claim 14.
Instant claim 15 recites wherein the duration of each of the consecutive treatment courses is about 2 weeks to about 6 weeks, and the interval between the consecutive treatment courses is about 2 week to about 6 weeks. Claim 9 of copending application ‘323 recites the duration of each of the consecutive treatment courses is about 2 weeks to about 6 weeks, and the interval between the consecutive treatment courses is about 2 week to about 6 weeks. The copending application anticipates instant claim 15.
Instant claim 16 recites wherein the interferon- based therapeutic agent is administered for 2-25 or more consecutive treatment courses. Claim 10 of copending application ‘323 recites the interferon-based therapeutic agent is administered for 2-25 or more consecutive treatment courses. The copending application anticipates instant claim 16.
Instant claim 17 recites wherein the durations of the plurality of consecutive treatment courses are substantially the same. Claim 11 of copending application ‘323 recites the durations of the plurality of consecutive treatment courses are substantially the same. The copending application anticipates instant claim 17.
Instant claim 18 recites wherein the intervals between the consecutive treatment courses are substantially the same. Claim 12 of copending application ‘323 recites the intervals between the consecutive treatment courses are substantially the same. The copending application anticipates instant claim 18.
Instant claim 19 recites wherein the cancer is selected from leukemia (such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia, polycapillary leukemia), liver cancer, lung cancer, colorectal cancer, skin cancer, stomach cancer, breastcancer, prostate cancer, non-Hodgkin's lymphoma, melanoma, multiple myeloma, laryngeal papilloma, follicular lymphoma, AIDS-related Kaposi's sarcoma and renal cell carcinoma, preferably liver cancer, lung cancer, breast cancer, colorectal cancer or melanoma. Claim 23 of copending application ‘323 recites the cancer is selected from leukemia (such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia, polycapillary leukemia), liver cancer, lung cancer, colorectal cancer, skin cancer, stomach cancer, breast cancer, prostate cancer, non-Hodgkin's lymphoma, melanoma, multiple myeloma, laryngeal papilloma, follicular lymphoma, AIDS-related Kaposi's sarcoma and renal cell carcinoma, preferably liver cancer, lung cancer, breast cancer, colorectal cancer or melanoma. The copending application anticipates instant claim 19.
Instant claim 21 recites wherein the additional anticancer agent is administered between the plurality of consecutive treatment courses. Claim 13 of copending application ‘323 recites the additional anticancer agent is administered after the first administration of the interferon-based therapeutic agent, the interval between the administration of the additional anticancer agent. The copending application anticipates instant claim 21.
Instant claim 23 recites wherein the additional anticancer agent is administered during and between plurality of consecutive treatment course. Claim 13 and 14 of copending application ‘323 recites, “the additional anticancer agent is administered… the interval between the administration of the additional anticancer agent” and “,the additional anticancer agent is administered during each consecutive treatment course, and the additional anticancer agent is administered after the interferon-based therapeutic agent during each consecutive treatment course”. The copending application anticipates instant claim 23.
Conclusion
16. No claims allowed
17. 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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached at 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SYED J ABBAS/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674