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 preliminary amendment filed 5/21/26 is acknowledged. Claims 1 and 16 have been amended. Claims 10 and 25 have been canceled. Claims 1-9, 11-24, and 26-30 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 1-9, 11-24, and 26-30 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 claims are drawn to a method of stimulating an immune cell, the method comprising an immune cell with an effective amount of a multi-chain chimeric polypeptide comprising:
(a) a first chimeric polypeptide comprising:
(i) a first target-binding domain;
(ii) a soluble tissue factor domain comprising a sequence that is at least 80% identical to SEQ ID NO:1; and
(iii) a first domain of a pair of affinity domains comprising a sequence that is at least 80% identical to SEQ ID NO: 14;
(b) a second chimeric polypeptide comprising:
(i) a second domain of a pair of affinity domains comprising a sequence that is at least 80% identical to SEQ ID NO:28; and
(ii) a second target-binding domain, wherein:
the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains; and
the first target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 11 and the second target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 78, or the first target-binding domain comprise a sequence that is at least 80% identical to SEQ ID NO: 78 and the second target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 11.
Although the claims are inclusive of a first chimeric polypeptide comprising SEQ ID NO: 104, and a second chimeric polypeptide comprising SEQ ID NO: 108, the claims also include fragments comprising amino acid sequences that have at least 90% or 95% identity to the polypeptide sequences set forth in SEQ ID NOs: 104 or 108. The claims also recite the component parts of the chimeric polypeptide. The first targeting domain comprises a first sequence (SEQ ID NO: 11) linked to a second sequence (SEQ ID NO: 14). The second targeting domain comprises a first sequence (SEQ ID NO: 78) linked to a second sequence (SEQ ID NO: 28). The soluble human tissue factor domain comprises the sequence set forth in SEQ ID NO: 1. Although the claims are inclusive of each of SEQ ID NOs: 1, 11 and 78, the claims also include fragments comprising amino acid sequences that have at least 90% or 95% identity to the polypeptide sequences set forth in SEQ ID NOs: 1, 11, 28 and 78. This would represent a large pool of variant polypeptides that must have similar functional activity. A variance, for example, in the polypeptide set forth in SEQ ID NO: 11 that is 152 amino acids in length translates into 30 residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 152 residue amino acid polypeptide. There is no limit in the claims, as written, that the variance be contiguous. Moreover, there is no limitation stating that the substitution, for example, be a conservative substitution. As a result, there are potentially thousands of variant permutations that could be made and still maintain a variance of 80%. Applicants have not described which domain or portions of SEQ ID NOs: 1, 11, 78, 104, or 108 that are critical to the function of the protein. The specification provides limited guidance regarding which amino acids can be modified in the genus of polypeptides, while maintaining any given function (i.e., stimulate an immune cell). Therefore, these structures (i.e. sequence variants) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e. critical domains within the sequences).
Thus, the genus of multi-chain chimeric polypeptides is extremely broad because the claims recite generic and incompletely described multi-chain chimeric polypeptides. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed chimeric polypeptides without adequate descriptions of its component parts or overall makeup. The generically claimed first-targeting binding domain that binds specifically to a receptor for IL-7, soluble tissue factor domain, first domain of a pair of affinity domains, a second domain of a pair of affinity domains, and a second target-binding domain that binds specifically to a receptor for IL-21 do not impart enough structural information to permit one of ordinary skill in the art to reasonably recognize or understand that Applicant was in possession of the full scope of the genus of chimeric polypeptides recited in the claims. For instance, without knowing the structure of the claimed first target-binding domain and the second target-binding domain, one would not be able to adequately describe the claimed polypeptide. Likewise, one of skill in the art would need to know the structures of the pair of affinity domains to describe the chimeric polypeptide. Although the specification teaches that the pair of affinity domains is a sushi domain from an alpha chain of human IL-15 receptor (IL15Rα) and a soluble IL-15, or the pair of affinity domains is selected from the group consisting of: barnase and barnstar, a PKA and an AKAP, adapter/docking tag modules based on mutated RNase I fragments, and SNARE modules based on interactions of the proteins syntaxin, synaptotagmin, synaptobrevin, and SNAP25, this is not a description of the specific portion of the aforementioned proteins that constitutes a pair of affinity domains that bind specifically to each other. The claims also recite a generic soluble tissue factor domain. The specification teaches that the tissue factor domain can be a wild type tissue factor polypeptide, peptide lacking the signal sequence, the transmembrane domain, and the intracellular domain. In some examples, the soluble tissue factor domain can be a tissue factor mutant, wherein a wild type tissue factor polypeptide lacking the signal sequence, the transmembrane domain, and the intracellular domain, and has been further modified at selected amino acids. In some examples, the soluble tissue factor domain can be a soluble human tissue factor domain. In some examples, the soluble tissue factor domain can be a soluble mouse tissue factor domain. In some examples, the soluble tissue factor domain can be a soluble rat tissue factor domain. However, this generic description of the soluble tissue factor is not a disclosure of the specific domain to be used in the chimeric polypeptide. Therefore, the specification does not provide adequate written description to identify the broad and variable genus of polypeptides because, inter alia, the specification does not disclose a correlation between the necessary structure of the polypeptide and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Accordingly, the specification does not define any structural features commonly possessed by members of the genus, because while the description of an ability of the claimed multi-chain chimeric polypeptide may generically describe the proteins function, it does not describe the multi-chain chimeric polypeptide itself. A definition by function does not suffice to define the genus because it is only an indication of what the multi-chain chimeric polypeptide does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of multi-chain chimeric polypeptide is highly variable (i.e. each chimeric polypeptide would necessarily have a unique structure; see MPEP 2434), the generic description of the multi-chain chimeric polypeptide is insufficient to describe the genus.
Further, applicants have not shown possession of a representative number of species of multi-chain chimeric polypeptides. As noted above, the claims are generic for the components of the chimeric polypeptide. Thus, there is substantial variation among the members of the genus because of the numerous options and combinations permitted. The claims recite a complete multi-chain chimeric polypeptide comprising SEQ ID NOs: 104 and 108; however, the claims encompass far more than this single species. Based on this lack of information within the specification, there is evidence that a representative number and a representative variety of structures of the multi-chain chimeric polypeptide that have the claimed functional properties have not yet been identified. Given the breadth of the genus, the disclosure of a few species is not deemed to be a sufficient number and/or variety of “representative species” for all of the other multi-chain chimeric polypeptides encompassed by the broad and variable generic claims. Therefore, the specification fails to disclose a sufficient description of a representative number and variety of multi-chain chimeric polypeptides within the genus. The specification does not provide substantive evidence for possession of this large and variable genus, encompassing a massive number of molecules claimed only by a functional characteristic. Accordingly, one of skill in the art would not conclude that Applicant was in possession of the claimed genus of multi-chain chimeric polypeptides.
The disclosure of only a few species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
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.)
Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al. and Burgess 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 multi-chain chimeric polypeptides could not be predicted based on sequence identity. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
Applicant has provided little or no descriptive support beyond the mere presentation of generic or partially named structures to enable one of ordinary skill in the art to determine the actual structural composition of the claimed genus of chimeric polypeptides. Although the prior art outlines art-recognized procedures for producing and screening for recombinant proteins this is not sufficient to impart possession of the genera of variant proteins to Applicant. Even if a few structurally identifiable composition components were described in the specification, they may not be sufficient, as the ordinary artisan would not necessarily immediately recognize how to put them together in such a way as to form a completely constructed chimeric polypeptide such that one would be able to distinguish it from the polypeptides of the prior art. Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of recombinant proteins as claimed.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed method which encompasses stimulating any immune cell, and treating any cancer, aging related condition, or infectious disease. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle& Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). 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).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claims 1-9, 11-24, and 26-30 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 stimulating CD4+ T cells, CD8+ T cells and NK cells comprising administering the multichain chimeric polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 104 and SEQ ID NO:108, does not reasonably provide enablement for a method of stimulating all immune cells and treating all cancers. 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 of stimulating an immune cell, the method comprising an immune cell with an effective amount of a multi-chain chimeric polypeptide comprising:
(a) a first chimeric polypeptide comprising:
(i) a first target-binding domain;
(ii) a soluble tissue factor domain comprising a sequence that is at least 80% identical to SEQ ID NO:1; and
(iii) a first domain of a pair of affinity domains comprising a sequence that is at least 80% identical to SEQ ID NO: 14;
(b) a second chimeric polypeptide comprising:
(i) a second domain of a pair of affinity domains comprising a sequence that is at least 80% identical to SEQ ID NO:28; and
(ii) a second target-binding domain, wherein:
the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains; and
the first target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 11 and the second target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 78, or the first target-binding domain comprise a sequence that is at least 80% identical to SEQ ID NO: 78 and the second target-binding domain comprises a sequence that is at least 80% identical to SEQ ID NO: 11.
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 multichain chimeric polypeptide for stimulating immune cells and treating cancer, 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.
The claims are broad and inclusive of all immune cells. The specification establishes the breadth of the term “immune cell” by teaching that the method comprises selecting the immune cell from the group consisting of: an immature thymocyte, a peripheral blood lymphocyte, a naïve T cell, a pluripotent Th cell precursor, a lymphoid progenitor cell, a Treg cell, a memory T cell, a Th17 cell, a Th22 cell, a Th9 cell, a Th2 cell, a Th1 cell, a Th3 cell, γδ T cell, an αβ T cell, a tumor-infiltrating T cell, a CD8+ T cell, a CD4+ T cell, a natural killer T cell, a mast cell, a macrophage, a neutrophil, a dendritic cell, a basophil, an eosinophil, and a natural killer cell. The specification further teaches that the immune cell is modified to express a chimeric antigen receptor or recombinant T cell receptor.
The claims are broad and inclusive of treating cancer, an aging-related disease or condition, or an infectious disease. The specification establishes the breadth of the claims by teaching the age-related disease or condition is selected from the group consisting of: Alzheimer's disease, aneurysm, cystic fibrosis, fibrosis in pancreatitis, glaucoma, hypertension, idiopathic pulmonary fibrosis, inflammatory bowel disease, intervertebral disc degeneration, macular degeneration, osteoarthritis, type 2 diabetes mellitus, adipose atrophy, lipodystrophy, atherosclerosis, cataracts, COPD, idiopathic pulmonary fibrosis, kidney transplant failure, liver fibrosis, loss of bone mass, myocardial infarction, sarcopenia, wound healing, alopecia, cardiomyocyte hypertrophy, osteoarthritis, Parkinson's disease, age-associated loss of lung tissue elasticity, macular degeneration, cachexia, glomerulosclerosis, liver cirrhosis, NAFLD, osteoporosis, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia, multiple sclerosis, and renal dysfunction.
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 establishes the breadth of the term “cancer” by teaching that the cancer is selected from the group consisting of: solid tumor, hematological tumor, sarcoma, osteosarcoma, glioblastoma, neuroblastoma, melanoma, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, B-cell neoplasms, multiple myeloma, B-cell lymphoma, B-cell non-Hodgkin's lymphoma, Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CMIL), acute lymphocytic leukemia (ALL), myelodysplastic syndromes (MDS), cutaneous T-cell lymphoma, retinoblastoma, stomach cancer, urothelial carcinoma, lung cancer, renal cell carcinoma, gastric and esophageal cancer, pancreatic cancer, prostate cancer, breast cancer, colorectal cancer, ovarian cancer, non-small cell lung carcinoma, squamous cell head and neck carcinoma, endometrial cancer, cervical cancer, liver cancer, and hepatocellular carcinoma.
The specification teaches the infectious disease is infection with human immunodeficiency virus, cytomegalovirus, adenovirus, coronavirus, rhinovirus, rotavirus, smallpox, herpes simplex virus, hepatitis B virus, hepatitis A virus, and hepatitis C virus, papillomavirus, and influenza virus. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed.
(5) The state of the prior art and (7) The predictability or unpredictability of the art
The state of the art regarding the role of IL-7 in tumor pathogenesis is discussed by Wang et al. (Cancer Commun (Lond). 2026 Jan 28;46:0008). Wang et al. teach that the role of IL-7 in tumor pathogenesis is controversial (See page 12). Wang et al. teach that the antitumor effects of IL-7 are primarily achieved by promoting the development and functional maintenance of antitumor immune cells by promoting B cell production and antibody formation; regulating T cell survival proliferation, differentiation, and activation; and maintaining NK cell homeostasis and activation status, while promoting DC differentiation (See page 12). Wang et al. teach that IL-7 also exerts its antitumor effects by regulating the immune cell release of antitumor cytokines, such as IFNγ, IL-1β, IL-1α, and TNF-α (See page 12). Wang et al. teach that IL-7 protects CD8+T cells by blocking the immunosuppressive effects of the adenosine pathway, thus enhancing their cytotoxic activity against tumor cells (See page 12). Wang et al. teach that the protumor effects of IL-7 are primarily manifested in directly promoting tumor cell proliferation and survival (See page 12). Wang et al. teach that binding of IL-7 to the IL-7R activates multiple signaling pathways that regulate the expression of Bcl-2 family genes, thereby promoting tumor cell proliferation and survival while inhibiting tumor cell apoptosis (See page 12). Wang et al. teach that IL-7 can rescue thymic CD4+CD8+ T cell subsets from apoptosis, which may potentially maintain tumor-associated immunosuppressive states under certain circumstances (See page 12). Wang et al. teach that function of IL-7 is highly dependent on the tumor. For example, in AML, IL-7 levels are typically elevated, primarily exerting protumor effects (See page 12). However, in solid tumors, IL-7 primarily exerts immune-supportive effects, but its role may switch as tumor progression and immune exhaustion intensify (See page 12).
Wang et al. teach that cytokines as therapeutic agents face numerous limitations in clinical application, including cytokine pleiotropy, complex biological properties, poor drug-like characteristics, and severe dose limiting toxicities (See page 15). Wang et al. teach that the roles that cytokines play in tumorigenesis depend specifically on tumor type and the TME, suggesting that researchers may need to employ cytokine activators or antagonists that target specific TMEs. Wang et al. teach that particularly noteworthy are cytokines with dual functions, which may exert different functions at different stages of tumor progression (See page 15). Wang et al. teach that another challenge confronting cytokine therapy is the heterogeneity of their distribution across different anatomical sites (See page 15). Wang et al. teach that this complexity in spatial distribution presents consider able difficulties in developing effective targeted therapeutic strategies (See page 15).
The state of the art regarding the significant of IL-7 and IL-7R in RA and autoimmunity is discussed by Meyer et al. (Autoimmun Rev. 2022 Jul;21(7):103120). Meyer et al. teach that the escalated concentration of IL-7 has been associated with autoimmune diseases, such as rheumatoid arthritis (See abstract). Meyer et al. teach that excessive levels of IL-7 were also detected in Spondyloarthritis (SpA) compared to osteoarthritis synovial fluid and tissue (See page 5). Meyer et al. teach that soluble IL7R has been found in higher levels in patients with SLE and teach that IL-7/IL-7R blockade may suppress the ability for immune cascades to instigate an inflammatory response (See pages 5-6). Meyer et al. teach that IL-7 levels are also markedly enriched in patients with psoriasis (See page 6).
The role of IL-21 in cancer immunotherapy is discussed by Stolfi et al. (OncoImmunology 1:3, 351–354; May/June 2012). Stolfi et al. teach that IL-21 is a drives anti-tumor immunity in the skin and kidney; however, is pro-inflammatory in many tissues and promotes colitis-associated colon cancer (See page 351). Stolfi et al. teach that the potent anti-tumor effects of IL-21 is due to its ability to expand the pool of cytotoxic CD8+ T cells, NK cells and NKT cells (See page 352). Stolfi et al. teach that before generally considering IL-21 an anti-tumor cytokine, it should be taken into consideration that the majority of the preclinical studies investigating the role of IL-21 in tumor development have been conducted on implanted tumor models and it remains unclear whether the anti-tumor activity of IL-21 can be generalized to spontaneously arising tumors, including those boosted by chronic inflammatory processes (See page 352). Stolfi et al. teach that a pro-inflammatory role of IL-21 has been described in psoriasis, rheumatoid arthritis, Type I diabetes, systemic lupus erythematosus, graft-vs. host disease, and inflammatory bowel diseases (IBD), and IL-21 blockers are now ready to move to the clinic (See page 352). Stolfi et al. teach that IL-21 is produced in excess not only in the mucosa of patients with UC, but also in the neoplastic areas of patients with UC-associated colon cancer and sporadic colorectal cancer (See page 352). Thus, the art demonstrates the function of IL-7 and IL-21 is dependent upon the disease setting, and there is no evidence that these results are broadly applicable to stimulating all immune cells and treating all cancers, aging-related disorders, and infectious diseases.
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 working examples disclose the IL-7/IL-15RαSu and IL-21/TF/IL-15 (21t15-7s) fusion protein. The working examples teach that cells stimulated with 21t15-7s complex caused expansion and activations of primary NK ells (See paragraph 0818-0819). The working examples teach that NK cells incubated with 21t15-7s showed increased cytotoxicity against K562 tumor cells (See paragraph 0820). The working examples disclose an exemplary IL-7/TF/IL-15:IL-21/IL-15RαSu protein complex (referred to as 7t15-21s). The working examples teach the complex causes expansion and activation of NK cells. The specification teaches 7t15-16s21 and IL-15 promoted 32Dβ cell proliferation. The specification teaches that overnight incubation of purified lymphocytes with 7t15-21s+anti-TF resulted in an increase in the percentage of CD8 and CD4 T cells expressing CD69 and CD62L (See paragraph 0979).
Thus, apart from a working example demonstrating that 21t15-7s and 7t15-21s stimulated CD4+ T cells, CD8+ T cells and NK cells, there is no guidance regarding stimulating any immune cell and treating any disease (cancer, aging-related disease or condition, or infectious disease) with the claimed multichain chimeric polypeptide. As a result, the practitioner would have to evaluate hundreds of immune cells to identify of possible cells amenable to treatment, resulting in undue experimentation to practice the invention. Similarly, the practitioner would have to evaluate hundreds of diseases and conditions to identify those amenable to treatment with the chimeric multichain polypeptide, resulting in undue experimentation.
(3) The relative skill of those in the art
The relative level of skill of those in the art is deemed to be high (e.g. PhD level); however, one of ordinary skill in the art could not predictably extrapolate the teachings in the specification to all of the specific diseases and conditions and subjects encompassed, as broadly claimed. The skilled artisan simply cannot envision the specific immune cells and diseases and conditions covered, thus conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method used to determine such diseases and conditions and/or subjects based on the interpretation of the claims as currently written. Thus, one of ordinary skill in the art, given its unpredictability (see state of the art above), would have to engage in undue experimentation to determine which immune cells can be stimulated in which subjects with the claimed multi-chain chimeric polypeptide and thereby carry out the invention as claimed.
(8) The quantity of experimentation
The specification does not enable the genus because where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims; In re Soil, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required; In re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity); see also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); and In re Vaeck, 947 F.2d 488,496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one particular species, what other species will work; see MPEP 2164.03. One of skill in the art would neither expect nor predict the immune cells, diseases and conditions, and subjects encompassed, as broadly as is claimed. Accordingly, without such guidance, the experimentation left to 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 USPQ 1016 (Fed. Cir. 1991) at 18 USPQ 1026 1027 and Exparte Forman, 230 USPQ 546 (BPAI 1986). Therefore, the scope of enablement provided to one skilled in the art is not commensurate with the scope of protection sought by the claims.
Therefore, in view of the lack of guidance and direction provided by Applicant there would be undue experimentation required to practice the invention, with a reasonable expectation of success, absent a specific and detailed description in Applicant's specification of how to effectively make and/or use the claimed invention. Thus, Applicant has not satisfied the requirements as set forth under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 4 recites the broad recitation CD4+ T cell, and the claim also recites Th17 cell, Th22 cell, Th9 cell, Th2 cell, Th1 cell, and Th3 cell, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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
Prosecution Insights