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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/16/25 has been entered.
Claim Status
The amendments and arguments filed 7/3/25 are acknowledged. Claim 4 is cancelled. New claim 16 is added. Claims 1-3 and 5-16 are pending. Claims 14-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/8/24. Claims 1, 8-9, and 11-13 are amended.
Claims 1-3, 5-13 and 16 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statement filed on 5/16/25 has been considered. A signed copy is enclosed.
Objections Withdrawn
The objection of claim 1 because of the following informalities: the phrase “selected in the group consisting of”, is not proper Markush language. It is recommended that the phrase be amended to read “selected from
Claim Rejections Withdrawn
The rejections of claims 9, 11, and 13 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention is maintained is withdrawn in light of Applicant’s amendments thereto. The rejection of claim 4 is rendered moot by cancellation of the claim.
Claim Rejections Maintained
Claim Rejections - 35 USC § 112(a)
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 rejection of claims 1-3, 5-13 and 16 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 is maintained. The rejection of claim 4 is rendered moot by cancellation of the claim. 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 pre-AIA 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 a method of treating cancer in a subject comprising administering a conjugate comprising a polypeptide comprising the amino acid sequence of IL-15 or derivatives thereof and a polypeptide comprising the amino acid sequence of IL-15alpha sushi domain or derivatives thereof. The "interleukin 15 derivatives" encompassed are not clear (see also rejection under 35 USC 112(b) below, but the claims refer to “derivative thereof having a substitution selected from the group consisting of L45D, L45E, S51D, L52D, N72D, N72E, N72A, N72S, N72Y and N72P”. the sushi domain “comprises SEQ ID NO:8, 9, or 12. The claims further specify a linker between the IL-15 and sushi domain comprising 5-30 amino acids.
The encompassed conjugate has several required functions, including treating all forms of cancer, inducing proliferation of natural killer cells at a same or higher level than HDIL-2, having at least 10% of the activity of human IL-15 on the proliferation induction of kit225 cell line, at least 10% of the binding activity of the sushi domain of IL-15Ralpha, inducing proliferation of CD8+ T cells higher than HDIL-2, inducing proliferation of Treg cells less than obtained with HDIL-2, and producing a threshold ratio of induced proliferating NK cells or proliferating CD8+ cells compared to on induced percentage of proliferating T reg cells.
One of skill in the art would not be able to predict the structure of the encompassed polypeptide conjugates that would correlate with these functions.
Specifically, the IL-15 derivatives are not defined according to the amended claims (see also the rejection under 35 USC 112(b) below).
The claim requires that the agent exhibit a number of functions, including inducing proliferation of NK cells and CD8 T cells at a level the same or higher than for HDIL-2, and treating cancer infection or an immunodeficiency disorder, but the specification provides no guidance regarding which conjugates and/or derivatives are capable of the required functions, except for the RLI conjugate, which is represented by SEQ ID NO:17 or 18. Therefore, there is no correlation between structure of the claimed agent and the function that is required for the claimed method.
The instant specification describes a suggested method for identifying the IL-15 and IL-15Ralpha derivatives that are capable of accomplishing the claimed functions. However, the skilled artisan cannot envision the detailed chemical structure of the encompassed biological and chemical molecules, 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 description of the molecule 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. 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.)
Further, the specification does not provide substantive evidence that any derivatives identified in the suggested screening method would be able to perform the functions set forth in the instant claims for the conjugate, with consideration given to chemical and physical properties of the agent. Predicting whether or not an agent will be able to treat a particular disease is fraught with obstacles, even if the patient population has a well-understood disease. As taught by Ma (Modern Drug Discovery 2004, 7(6)), in vitro assays typically rely on simple interactions of chemicals with a drug target, but any results from in vitro screening often poorly correlate with in vivo results because the complicated physiological environment is absent in the in vitro system (see page 30, left column). For the skilled artisan to practice the claimed invention, a full description of the structural features that would cause a conjugate to meet the claimed functional limitations, including treating the claimed vast range of diseases and inducing cell proliferation, is required. Without this demonstration, the skilled artisan would not be able to reasonably predict the outcome of the claimed method, i.e. would not be able to accurately predict if an identified conjugate would be able to perform the functions in the claimed method.
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.
Protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) As taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
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 Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). 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).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the conjugates that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of the instant claims.
Given the teachings of these references that point out the limitations and pitfalls of using sequence to predict functions, and the lack of a representative number of species across the breadth of the genus, one of skill in the art would not reasonably conclude that Applicant had possession of the full breadth of the claims, or meet the written description provision of 35 USC 112(a).
The polypeptide conjugates of the instant application are all required to have a particular function as an immunocytokine, with each portion of the molecule having a specific required function such as being an IL-15 agonist or superagonist, or having binding activity of the sushi domain of human IL-15Ralpha. Further, the conjugate itself, within the context of the claimed method, must be able to treat all cancers, infections, and immunodeficiencies, as well as induce cell proliferation of at least two different immune cell types. But the claims encompass a vast number of possible polypeptide conjugates, with an extremely large number of possible variants and there is no guidance in the specification as to which variant polypeptides of the conjugate would maintain the required functions. To give an idea of the vast breadth of the genus, selecting any 9 amino acids from the 114 amino acids of SEQ ID NO:3 to mutate (which would fall within the 92.5% sequence identity) would yield more than 1.5x1015 possible proteins. It is well known in the art that any single amino acid change can result in completely altering the binding between two polypeptides or disrupt function in any given domain. This means that while there is 92-92.5% similarity, the 7.5-8% difference is extraordinarily important. It is also well known that the results of changing any given amino acid are entirely unpredictable. Therefore, with no guidance from the specification, those of skill in the art, and even applicants themselves have no idea whatsoever which of the thousands polypeptides encompassed by the about 92% similarity will have the function required by the claims. Further, it seems self-evident that altering amino acids within the polypeptides, especially known binding domains, will alter the binding.
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. The Guidelines for Examination of Patent Applications under the 35 USC §112 paragraph 1, “Revision 1” of Written Description Requirement (66 FR 1099-1111, March 25, 2008) state, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the Applicant was in possession of the claimed invention (ld. At 1104). 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.
Applicant’s Arguments
Applicant argues:
1.Applicant argues that the claims have been amended to address the rejection. The conjugate has been limited to a conjugate “consisting of” an IL-15 component, sushi domain, and a linker. Thus fusion proteins with additional moiety is excluded from the scope of the claim. Further, any derivatives of the IL-15Ralpha sushi domain have been deleted from the claim scope, and the derivatives have been limited to specific amino acid substitutions.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
The rejection is maintained because the IL-15 derivatives are not clearly defined. The IL-15 of SEQ ID NO:3, IL-15Ralpha of SEQ ID NO:8, 9, and 12, and the linker are adequately described. However, it is unclear if the derivatives of IL-15 are limited to SEQ ID NO:3 with the mutations listed in the claim. As stated below, claim 3 recites “an amino acid sequence having a percentage of identity of at least 98.5% with the amino acid sequence of SEQ ID NO:3. This claim suggests that the IL-15 is not limited to only proteins having SEQ ID NO:3 with one of the named mutations, and therefore, the conjugates encompassing the IL-15 are not adequately described. When given the broadest reasonable interpretation based on the claims as amended, the IL-15 can comprise any sequence derived from SEQ ID NO:3, as long as one of the specifically named mutations is present. These polypeptides are not adequately described. Therefore the rejection is maintained for these reasons and the reasons set forth above.
Enablement
The rejection of claims 1-3, 5-13 and 16 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of non-metastatic melanoma and renal cell carcinoma with the RLI conjugate molecule, does not reasonably provide enablement for treatment of any infection, any immunodeficiency, or all encompassed cancers with all of the encompassed conjugates is maintained. The rejection of claim 4 is rendered moot by cancellation of the claims. 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.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (5) The breadth of the claims:
The claims are drawn to a method for treating diseases including all cancers, comprising administering to a subject a conjugate comprising an IL-15 molecule or derivatives thereof, and the sushi domain of an IL-15Ralpha or derivatives thereof. The method administers an amount of the conjugate sufficient to induce proliferation of natural killer, Treg, and CD8+ T cells that is the same or higher as that seen when administering high dose of IL-2. The claims recite various ranges for proliferation and dosages.
The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The instant claims are drawn to a method of treating cancer in a subject comprising administering a conjugate comprising a polypeptide comprising the amino acid sequence of IL-15 or derivatives thereof and a polypeptide comprising the amino acid sequence of IL-15alpha sushi domain or derivatives thereof. The "interleukin 15 derivatives" encompassed are not clear (see also rejection under 35 USC 112(b) below, but the claims refer to “derivative thereof having a substitution selected from the group consisting of L45D, L45E, S51D, L52D, N72D, N72E, N72A, N72S, N72Y and N72P”. The sushi domain “comprises SEQ ID NO:8, 9, or 12. The claims further specify a linker between the IL-15 and sushi domain comprising 5-30 amino acids.
It is also noted that the instant specification defines treatment as “reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.” Therefore both therapeutic and prophylactic treatment of the diseases is encompassed.
Further, the claims are extremely broad due to the vast number of diseases encompassed. 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. Several assorted categories of example tumor types was provided in the previous Office Action, and remain relevant to the maintained rejection. Applicant should note that the categories have been removed only for concision, but the breadth of the categories of encompassed tumor types still applies for the purposes of this rejection.
(2) The state of the prior art and (4) 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 regard to treating all of the encompassed disorders broadly is underdeveloped. In particular, there is no known agent that is effective against all of the encompassed diseases and disorders. The disease treatment art involves a very high level of unpredictability. While the state of the art is relatively high with regard to the treatment of specific cancers with specific agents, it has long been underdeveloped with regard to the treatment of all diseases broadly. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of the encompassed disorders in a subject, with the claimed active ingredient makes practicing the claimed invention unpredictable.
Predicting whether or not an agent will be able to treat a particular disease is fraught with obstacles, even if the patient population has a well-understood disease. As taught by Ma (Modern Drug Discovery 2004, 7(6)), in vitro assays typically rely on simple interactions of chemicals with a drug target, but any results from in vitro screening often poorly correlate with in vivo results because the complicated physiological environment is absent in the in vitro system (see page 30, left column). In vitro and animal model studies have not correlated well with in vivo clinical trial results in patients. Since the therapeutic indices of biopharmaceutical drugs can be species- and model-dependent, it is not clear that reliance on the in vitro and in vivo experimental observations with a single example of the encompassed conjugates, accurately reflects the relative ability or efficacy of the claimed methods treat all of the encompassed diseases. Pharmaceutical therapies in the absence of in vivo clinical data are unpredictable for the following reasons; (1) the protein may be inactivated before producing an effect, i.e. such as proteolytic degradation, immunological inactivation or due to an inherently short half-life of the protein; (2) the protein may not reach the target area because, i.e. the protein may not be able to cross the mucosa or the protein may be adsorbed by fluids, cells and tissues where the protein has no effect; and (3) other functional properties, known or unknown, may make the protein unsuitable for in vivo therapeutic use, i.e. such as adverse side effects prohibitive to the use of such treatment. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).
The specification does not adequately teach how to effectively extrapolate data obtained from in vitro models, or a single mouse model of administration of a single conjugate species to all genera of diseases and/or conjugates encompassed. Without these teachings, one of skill in the art would require undue experimentation to practice the claimed methods of with a reasonable expectation of success, absent a specific and detailed description in applicant's specification of how to effectively practice the claimed methods and absent working examples providing evidence which is reasonably predictive that the claimed methods are effective for all of the encompassed diseases with all of the encompassed conjugates.
As an example of the extremely broad nature of the encompassed diseases, with regard to cancer treatment, Bally et al. (US 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” (col. 1, lines 17-24).
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 teaches 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) indicates 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, encloses 1-5) 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.
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.
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 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 indicates that there are 3 critical tasks that drugs must do to attack malignant cells in a tumor: 1) it has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, 2) exit from the vessel into the surrounding matrix, and 3) migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps (see p. 58, bottom of right most column). Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254) states that “The past three decades have seen spectacular advances in our understanding of the molecular and cellular biology of cancer. However, with a few notable exceptions, such as the treatment of chronic myeloid leukemia with imatinib, these advances have so far not been translated into major increases in long-term survival for many cancers. Furthermore, data suggest that the overall success rate for oncology products in clinical development is -10%, and the cost of bringing a new drug to market is over US$1 billion.” (see page 253, left column, the 1st paragraph). Hait further teaches “The anticancer drug discovery process often begins with a promising target; however, there are several reasons why the eventual outcome for a particular cancer target may be disappointing. For example, the role of the target in the pathogenesis of specific human malignancies may be incompletely understood, leading to disappointing results”, “First, many targets lie within signal transduction pathways that are altered in cancer, but, owing to the complex nature of these pathways, upstream or downstream components may make modulating the target of little or no value”; “Second, target overexpression is often overrated. There are some instances in which overexpression predicts response to treatment.”; and “Another confounding factor is that cancer is more than a disease of cancer cells, as alterations in somatic or germline genomes, or both, create susceptibilities to transformational changes in cells and in the microenvironment that ultimately cooperate to form a malignant tissue. The putative role of cancer stem cells in limiting the efficacy of cancer therapeutics is also an area of intense interest. Therefore, effective treatments may require understanding and disrupting the dependencies among the multiple cellular components of malignant tissues. Single nucleotide polymorphisms in genes responsible for drug metabolism can further complicate the picture by affecting drug pharmacokinetics; for example, as with the topoisomerase inhibitor irinotecan.”, for example, page 253, Section “Understanding the target in context”. Hait also teaches “Drug effects in preclinical cancer models often do not predict clinical results, as traditional subcutaneous xenografting of human cancer cell lines onto immunocompromised mice produces ‘tumors’ 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 hematopoietic and immune systems. Newer genetic mouse models can also allow analyses of tumor 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 presented; (7) the presence or absence of working examples:
The instant specification provides examples of administration for a single conjugate encompassed by the claims, wherein the conjugate is RLI. The conjugate RLI was administered to mice with melanoma and renal cell carcinoma. The injections indicated decrease in primary tumor growth for both xenograft types, and inhibition of lung metastasis for the renal carcinoma. The specification does not demonstrate administration of any other encompassed conjugate, administration to any subject with an infection or immunodeficiency, or administration to a subject with any other cancer.
In conclusion, the claimed invention does not provide enablement for all embodiments of the claimed method. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Applicant’s Arguments
Applicant argues:
1. Applicant has pointed to data in the specification involving in vitro experiments that show conjugate effects on NK and CD8+ T cells. Applicant argues that “a stimulation of NK cells and CD8+T cells causes an upregulation of the immune system which is beneficial for treating any type of cancer.”
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
The claims must be evaluated as a whole to determine if the method is enabled (see MPEP 2164). In the instant application, the method as a whole is not enabled and one of skill in the art would be required to engage in undue experimentation to practice the method.
Applicant is improperly extrapolating findings related to a single conjugate in a limited number of in vitro experiments to administration of an enormous genus of possible conjugates for the purposes of treating thousands of possible diseases. Example 1 shows testing of the single species of RLI conjugate on PBMCs taken from healthy donors and from healthy mouse NK cells. Notably, only a single conjugate out of billions was tested, and experiments used healthy cells, not cells from diseased individuals. There is no way to draw any conclusions about the therapeutic effect of any conjugate, including RLI, when the experiments showing activity were conducted in cells from individuals that do not have any of the encompassed diseases. Another example shows testing of RLI in mice, where RLI was tested for safety, and measured proliferation of effector cells as compared to IL-2 and IL-15. Additional safety studies were performed in macaque testing RLI pharmacokinetics over a dose range. However, again it is noted that none of these animals were diseased. These studies show only safety and in vitro effects, without actually administering any conjugate to any diseased subject for the purposes of therapeutic effect. Even when the results are construed broadly, at best the examples only demonstrate the in vitro and in vivo effects of a single conjugate encompassed by the instant claims (i.e. RLI), and not for any of the billions of other conjugates encompassed by the claims.
As stated above, the only testing in subjects with encompassed disorders included examples of administration for a single conjugate encompassed by the claims (i.e. RLI). The conjugate RLI was administered to mice with melanoma and renal cell carcinoma. The injections indicated decrease in primary tumor growth for both xenograft types, and inhibition of lung metastasis for the renal carcinoma. Therefore treatment of non-metastatic melanoma and renal cell carcinoma with the RLI conjugate molecule is considered enabled as indicated above. The specification does not demonstrate administration of any other encompassed conjugate, or administration to a subject with any other cancer.
Applicant also relies on a merely conclusory statement that “a stimulation of NK cells an