DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment filed 2/6/24 is acknowledged. Claims 1-88 have been canceled. Claims 89-109 have been added. Claims 89-109 are pending and under examination.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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.
Claims 89-109 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 issue with regards to the written description provision of 35 USC112(a) is that the claims encompass a vast genus of RNAs encoding an IL-12sc, an mRNA encoding IL-15 sushi, an mRNA encoding IFNα, and an mRNA encoding GM-CSF that are not adequately described. Some claim embodiments encompass an RNA encoding an IL-12sc protein comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 14. The claims encompass an RNA encoding an IL-15 sushi protein comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 24. The claims encompass an RNA encoding an IFNα protein comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 19. The claims encompass an RNA encoding a GM-CSF protein comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 27. The claims further recite wherein each RNA comprises a modified nucleoside in place of each uridine, wherein the modified nucleoside is pseudouridine, N1-methyl-pseudouridine, 5-methyl-uridine, or a combination thereof.
The specification teaches that mRNAs encoding IL-12sc, IL-15 sushi, IFNα, and GM-CSF were modified with mod A (SEQ ID NOs: 32, 38, 50, and 56) or mod B (SEQ ID NOs: 35, 41, 47, 53, and 59), and the combination of modified mRNAs caused tumor regression when injected into mice expressing B16F10 or CT26 tumor. The specification discloses mRNA encoding the human cytokines IL-15 sushi, IL-12sc, GM-CSF, and IFNα and teaches that each of the mRNAs was modified with ModB.
Although the claims are inclusive of the IL-12sc protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 14 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO: 17 or 18, the IL-15 sushi protein comprising the full-length amino acid sequence sequence set forth in SEQ ID NO: 24 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO:26 , the IFNα protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 19 and encoded by the full-length nucleotide sequence set forth in SEQ ID NOs: 22 or 23 , and the GM-CSF protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 27 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO: 29, the claims also broadly encompass variants that share 95% sequence identity to the aforementioned sequences. This indicates there are hundreds, if not thousands of potential protein and nucleotide sequences encompassed by the claims. For example, considering only the IL-12sc protein set forth in SEQ ID NO: 14, a 5% variance in the amino acid sequence set forth in SEQ ID NO: 14, which is 539 amino acid residues in length, would allow for up to 26 substitutions in the sequence. Likewise, considering the IL-12sc nucleotide sequence of SEQ ID NO: 17 (1623 nucleotides), a variance of 5% would allow for up to 54 substitutions in the nucleotide sequence, resulting in up to 18 amino acid differences in the final polypeptide. Furthermore, neither the claims nor the specification specifies what residues can be substituted, therefore, it can be considered that the nucleotide sequences encompass thousands of possible substitutions (i.e., one substitution per codon, or a string of substitutions). Therefore, the claims encompass millions of possible mRNAs and nucleic acids, some of which may have significant sequence alterations from the recited mRNAs and nucleic acids. These mRNAs and nucleic acids have no correlation between their structure and the function of treating or reducing the likelihood of a solid tumor.
Additionally, 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 IL-12sc protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 14 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO: 17 or 18, the IL-15 sushi protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 24 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO:26 , the IFNα protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 19 and encoded by the full-length nucleotide sequence set forth in SEQ ID NOs: 22 or 23 , and the GM-CSF protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 27 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO: 29, and the claimed function(s), 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 sequences and encompass variants sharing 95% sequence identity to the claimed sequences. 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 a few species have been described and this is not considered to be representative of the breadth of the genus.
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 IL-12sc protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 14 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO: 17 or 18, the IL-15 sushi protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 24 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO:26 , the IFNα protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 19 and encoded by the full-length nucleotide sequence set forth in SEQ ID NOs: 22 or 23 , and the GM-CSF protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 27 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO: 29, the skilled artisan cannot envision the detailed chemical structure of the encompassed agents, 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 USPQ2datl966.
It is well understood in the art that multiple codons can code for the same amino acid. However, the instant specification does not specify that the 5% variation has no effect on the final amino acid sequence due to the redundancy of the genetic code, or only conservative amino acid changes are allowed. It is well known that protein folding and formulation are complex and fairly unpredictable processes, in such that substituting even one amino acid within the sequence can change the structure and function of said protein. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) 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).
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 survivin results in the conversion of survivins’ 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., 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 could not be predicted based on sequence identity to SEQ ID NO: 14, 24, 19, 27, 17, 18, 26, 22, 23, or 29. Clearly, it could not be predicted that nucleic acids or a variant that shares only partial homology with a disclosed sequence or that is a fragment of a given SEQ ID NO. will function in a given manner (i.e. treat or reduce the likelihood of a solid tumor). Therefore, only amino acid and nucleotide sequences consisting of the sequences shown in SEQ ID NO: 14, 24, 19, 27, 17, 18, 26, 22, 23, or 29, but not the full breadth of the claims, meet the written description provision of 35 USC 112, first paragraph.
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.
Claims 89-109 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating melanoma, colon cancer, breast cancer comprising administering the mRNA mixture of the IL-12sc protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 14 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO: 17 or 18, the IL-15 sushi protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 24 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO:26 , the IFNα protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 19 and encoded by the full-length nucleotide sequence set forth in SEQ ID NOs: 22 or 23 , and the GM-CSF protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 27 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO: 29, does not reasonably provide enablement for treating, or reducing the likelihood of all tumors. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability, 5) existence of working samples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
1) Nature of the invention and 6) Breadth of the claims
The nature of the invention is a method for treating, or reducing the likelihood of, a solid tumor comprising administering to a subject in need thereof a composition comprising RNA encoding an IL-12sc protein, RNA encoding an IL-15 sushi protein, RNA encoding an IFNa protein, and RNA encoding a GM-CSF protein, wherein each RNA comprises a modified nucleoside in place of each uridine, wherein the modified nucleoside is pseudouridine (V), N1-methyl-pseudouridine (mly), 5-methyl-uridine (m5U), or a combination thereof, and wherein the IL-12sc protein comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 14; the IL-15 sushi protein comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 24 the IFNa protein comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 19; and the GM-CSF protein comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 27.
Therefore, the nature of the invention is a chemical case, wherein there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; See MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to make and use the claimed mRNA combination for treating or reducing the likelihood of a solid tumor, with a reasonable expectation of success, because it would not be predictable from the disclosure of any particular species what other species may or may not work; See MPEP 2164.03.
Although the claims are inclusive of the IL-12sc protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 14 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO: 17 or 18, the IL-15 sushi protein comprising the full-length amino acid sequence sequence set forth in SEQ ID NO: 24 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO:26 , the IFNα protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 19 and encoded by the full-length nucleotide sequence set forth in SEQ ID NOs: 22 or 23 , and the GM-CSF protein comprising the full-length amino acid sequence set forth in SEQ ID NO: 27 and encoded by the full-length nucleotide sequence set forth in SEQ ID NO: 29, the claims also broadly encompass variants that share 95% sequence identity to the aforementioned sequences. This indicates there are hundreds, if not thousands of potential protein and nucleotide sequences encompassed by the claims. For example, considering only the IL-12sc protein set forth in SEQ ID NO: 14, a 5% variance in the amino acid sequence set forth in SEQ ID NO: 14, which is 539 amino acid residues in length, would allow for up to 26 substitutions in the sequence. Likewise, considering the IL-12sc nucleotide sequence of SEQ ID NO: 17 (1623 nucleotides), a variance of 5% would allow for up to 54 substitutions in the nucleotide sequence, resulting in up to 18 amino acid differences in the final polypeptide. Furthermore, neither the claims nor the specification specifies what residues can be substituted, therefore, it can be considered that the nucleotide sequences encompass thousands of possible substitutions (i.e., one substitution per codon, or a string of substitutions). Therefore, the claims encompass millions of possible mRNAs and nucleic acids, some of which may have significant sequence alterations from the recited mRNAs and nucleic acids. These mRNAs and nucleic acids have no correlation between their structure and the function of treating or reducing the likelihood of a solid tumor.
The claims also broadly encompass treating or reducing the likelihood of any solid tumor. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. For example, there are solid cancers of the brain, spine, live, prostate, testes, ovaries, bile duct, blood vessels, lung and pleural cavity, thyroid, skin (including melanoma), colon, prostate, kidneys, breasts, testicles, vulva and vagina, uterus, cervix, fallopian tubes, thymus, stomach, esophagus, spleen, salivary glands, heart, oral cavity, adrenal glands, eye, head and neck, bladder, bone, and gall bladder. Each of these types of cancer have potentially dozens of sub-categories that each have unique physiological and etiological characteristics.
The specification also establishes the breadth of the claims by teaching that the solid tumor is in the lung, colon, ovary, cervix, uterus, peritoneum, testicles, penis, tongue, lymph node, pancreas, bone, breast, prostate, soft tissue, connective tissue, kidney, liver, brain, thyroid, or skin. The specification further teaches that the solid tumor is an epithelial tumor, Hodgkin lymphoma (HL), non-Hodgkin lymphoma, prostate tumor, ovarian tumor, renal cell tumor, gastrointestinal tract tumor, hepatic tumor, colorectal tumor, tumor with vasculature, mesothelioma tumor, pancreatic tumor, breast tumor, sarcoma tumor, lung tumor, colon tumor, brain tumor, melanoma tumor, small cell lung tumor, neuroblastoma tumor, testicular tumor, carcinoma tumor, adenocarcinoma tumor, glioma tumor, seminoma tumor, retinoblastoma, or osteosarcoma tumor.
(5) The state of the prior art and (7) The predictability or unpredictability of the art
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 anticancer agent that is effective in treating or preventing all cancer cell types. The cancer treatment art involves a very high level of unpredictability. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all cancer cells in a mammal, including a human subject, with the claimed active ingredient makes practicing the claimed invention unpredictable.
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). Beans 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.
6) The amount of direction or guidance provided by the inventor; 7) The existence of working examples:
The specification teaches that mRNAs encoding IL-12sc, IL-15 sushi, IFNα, and GM-CSF were modified with mod A (SEQ ID NOs: 32, 38, 50, and 56) or mod B (SEQ ID NOs: 35, 41, 47, 53, and 59), and the combination of modified mRNAs caused tumor regression when injected into mice expressing B16F10 or CT26 tumor. The specification discloses mRNA encoding the human cytokines IL-15 sushi, IL-12sc, GM-CSF, and IFNα and teaches that each of the mRNAs was modified with ModB.
The specification teaches that the combination of four mRNAs reduce tumor volume size. The specification teaches that the cytokine mRNA mixtures encoding: i) GM-CSF, IL-2, IL-12sc (SEQ ID NOs: 59, 35, and 41; FIG. 5A), ii) GM-CSF, IL-15 sushi, IL-12sc (SEQ ID NOs: 59, 53, and 41; FIG. 5B) and iii) GM-CSF, IL-15 sushi, IL-12sc, IFNα (SEQ ID NOs: 59, 53, 41, and 47; FIG. 5C) each had an anti-tumor effect in the B16F10 tumor model, with 4 out of 8 tumors regressing following intratumoral injection of cytokine mRNA mixtures of GM-CSF, IL-2, and IL-12sc or GM-CSF, IL-15 sushi, and IL-12sc, and 7 out of 8 tumors regressed upon treatment with GM-CSF, IL-15 sushi, IL-12sc, and IFNα (See example 3). The specification teaches that the anti-tumor activity of GM-CSF, IL-2, IL-12sc, and IFNα was examined in three different murine in vivo tumor models, CT26, B16F10 and MC38. Tumor bearing mice received 4-6 intratumoral injections of ModB cytokine mRNA encoding IL-2, IL-12sc, GM-CSF and IFNα (SEQ ID NOs: 35, 41, 59, and 47) or a control ModB mRNA encoding firefly luciferase. Anti-tumor activity was assessed in each tumor model. Mice treated with this combination of cytokine mRNA had 4/8, 7/8 and 5/5 regressing tumors in the CT26 (FIG. 6A), B16F10 (FIG. 6C) and MC38 (FIG. 6E) models, respectively (See example 3). The specification teaches that the anti-tumor activity of a four-component cytokine mRNA mixture encoding each of IL-2, IL-12sc, GM-CSF and IFNα (ModB, SEQ ID NOs: 35, 41, 59, and 47) or IL-15 sushi, IL-12sc, GM-CSF and IFNα (ModB, SEQ ID NOs: 53, 41, 59, and 47) was evaluated in the CT26 tumor model. Tumor bearing mice were treated with 6 intratumoral injections and tumor growth was monitored. Treatment with both IL-2, IL-12sc, GM-CSF and IFNα (FIG. 7A) and IL-15 sushi, IL-12sc, GM-CSF and IFNα (FIG. 7B) effectively induced tumor regression in 4/8 and 8/8 mice, respectively, while no tumor regressions were observed for mice treated with the control mRNA (FIG. 7C). The specification teaches that the cytokine mRNA mixtures protect against tumor re-challenge (See example 4). The specification teaches that B16F10 tumor bearing mice were treated with a cytokine mRNA mixture of IL-15sushi, IL-12sc, GM-CSF, and IFNα (Mod B; SEQ ID NOs: 53, 41, 59, and 47). A portion of the cytokine mRNA treatment B16F10 tumors completely regressed leading to tumor free animals. These tumor free animals were then re-challenged with B16F10 cells as a way to assess adaptive immune memory and 9 naïve mice were implanted with B16F10 tumor cells as a positive control for tumor engraftment (FIG. 12A). All 9 naïve mice engrafted with B16F10 cells developed tumors, whereas all eight tumor-free mice rejected the B16F10 cells and did not exhibit growth of B16F10 tumors (FIG. 12B) (See example 4). The specification teaches that the cytokine mRNA mixture encoding IL-15 sushi, IL-12sc, GM-CSF and IFNα (ModB; SEQ ID NOs: 53, 41, 59, and 47) caused dose-dependent anti-tumor activity in both injected and uninjected tumors with tumor growth inhibition ranging from 88% in the uninjected tumor to 96% in the injected tumor (See example 5).
Thus, apart from a working example demonstrating that the cytokine mixture encoding IL-15 sushi, IL-12sc, GM-CSF and IFNα (ModB; SEQ ID NOs: 53, 41, 59, and 47) demonstrated anti-tumor activity in CT26, B16F10 and MC38 tumor models, there is no guidance regarding treating or reducing the likelihood of a solid tumor with the claimed cytokine mRNA mixture. As a result, the practitioner would have to evaluate hundreds of tumors to identify tumors amenable to treatment with the claimed cytokine mixture, resulting in undue experimentation.
Taken together, the art demonstrates that treatment of cancer is highly unpredictable, if even impossible for many cancers. Moreover, the art provides evidence that the heterogeneity of tumors contributes to the variability in treating cancer. Accordingly, it follows those solid tumors that can be treated with the claimed cytokine mRNA mixture can only be identified empirically. This constitutes undue experimentation. Therefore, given the lack of guidance in the art, the lack of working examples commensurate in scope to the claimed invention and the unpredictability of cancer therapy, the specification, as filed does, not provide enablement for the claimed genus of solid tumors.
Applying the above test to the facts of record, it is determined that 1) no declaration under 37 C.F.R. 1.132 or other relevant evidence has been made of record establishing the amount of experimentation necessary, 2) insufficient direction or guidance is presented in the specification with respect to broadly treating or reducing the likelihood of any solid tumor with the claimed cytokine mRNA mixture, 3) the relative skill of those in the art is commonly recognized as quite high (post-doctoral level). One of skill in the art would require guidance, in order to make or use the claimed cytokine mRNA mixture to treat the vast genus of solid tumors in a manner reasonable in correlation with the scope of the claims. Without proper guidance, the experimentation to is undue.
The Applicant has not provided sufficient guidance to enable one of skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including all solid tumors. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, determining solid tumors that can be treated with the claimed cytokine mRNA mixture is unpredictable and the experimentation left those skilled in the art is unnecessarily and improperly, extensive and undue. See Amgen Inc v Chugai Pharmaceutical Co Ltd. 927 F 2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991) at 18 USPQ2d 1026-1027 and Exparte Forman, 230 U.S.P.Q. 546(Bd. Pat=. App & int. 1986).
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph.
Claim Status
No claims are allowed.
Conclusion
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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