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 .
Claims 1-22 are pending and under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). (See pages 453-458aand 472-475) The entire specification should be checked for these errors and correction is required.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
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 1-22 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 treating a subject identified or diagnosed as having an infectious disease, the method comprising administering to the subject a therapeutically effective amount of a multi-chain chimeric polypeptide, wherein the multi-chain chimeric polypeptide comprises:
(a) a first chimeric polypeptide comprising:
(i) a first target-binding domain;
(ii) a soluble tissue factor domain; and
(iii) a first domain of a pair of affinity domains;
(b) a second chimeric polypeptide comprising:
(i) a second domain of a pair of affinity domains; 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. The dependent claims state that the tissue factor domain comprises a sequence that is at least 80% identical to SEQ ID NO: 1. The dependent claims states that the soluble human tissue factor domain comprises a sequence that is at least 90% identical to SEQ ID NO: 1. The dependent claims states that the alpha chain of human IL-15Ra comprises a sequence that is at least 90% identical to SEQ ID NO: 28. The dependent claims state that the soluble human IL-15 comprises a sequence that is at least 90% identical to SEQ ID NO: 14. The dependent claims state that the first target-binding domain and the second target-binding domain each comprise a sequence that is at least 90% identical to SEQ ID NO: 85. The dependent claims state that the first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 85; the soluble tissue factor domain comprises a sequence that is at least 90% identical to SEQ ID NO: 1; and the first domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 14; the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 85; and the second domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 28. The dependent claims state the first target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 85; the soluble tissue factor domain comprises a sequence that is at least 95% identical to SEQ ID NO: 1; and the first domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 14; the second target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 85; and the second domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 28. The dependent claims state that the first chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 133; and the second chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 177. The dependent claims state that the first chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 133; and the second chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 177.
Although the claims are inclusive of a first chimeric polypeptide comprising SEQ ID NO: 133, and a second chimeric polypeptide comprising SEQ ID NO: 177, 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: 133 or 177. The claims also recite the component parts of the chimeric polypeptide. Although the first and second target-binding domain claims are inclusive of each of SEQ ID NOs: 85, the soluble tissue factor is inclusive of SEQ ID NO:1, the first domain of the pair of affinity domain comprises SEQ ID NO: 14 and the second domain of the pair of affinity domain comprises SEQ ID NO: 28, 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: 85, 1, 14,and 28. This would represent a large pool of variant polypeptides that must have similar functional activity. A variance of 10%, for example, in the polypeptide set forth in SEQ ID NO: 85 that is 287 amino acids in length translates into 28 residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 287 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 90%. Applicants have not described which domain or portions of SEQ ID NOs: 85, 1, 14, 28, 133, or 177 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., treat an infectious disease). 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 ligand of TGFβRII, 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 ligand of TGFβRII 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. The claims recite a complete multi-chain chimeric polypeptide comprising SEQ ID NOs: 133 and 177; however, the claims encompass far more than this single species. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163). Thus, the specification does not provide adequate guidance to carry out the claimed method commensurate in scope with the claims such that the recited agents can be used to treat any cancer.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
With the exception of the multichain chimer polypeptide comprising SEQ ID NO: 133 and SEQ ID NO: 177 , the skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601,1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2dl961,1966 (1997); In re Gosteli, 872 F.2dl008,1012,10 USPQ2dl614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in 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 treating any cancer. 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 1-22 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
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 treating a subject identified or diagnosed as having an infectious disease, the method comprising administering to the subject a therapeutically effective amount of a multi-chain chimeric polypeptide, wherein the multi-chain chimeric polypeptide comprises:
(a) a first chimeric polypeptide comprising:
(i) a first target-binding domain;
(ii) a soluble tissue factor domain; and
(iii) a first domain of a pair of affinity domains;
(b) a second chimeric polypeptide comprising:
(i) a second domain of a pair of affinity domains; 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. The dependent claims state that the tissue factor domain comprises a sequence that is at least 80% identical to SEQ ID NO: 1. The dependent claims states that the soluble human tissue factor domain comprises a sequence that is at least 90% identical to SEQ ID NO: 1. The dependent claims states that the alpha chain of human IL-15Ra comprises a sequence that is at least 90% identical to SEQ ID NO: 28. The dependent claims state that the soluble human IL-15 comprises a sequence that is at least 90% identical to SEQ ID NO: 14. The dependent claims state that the first target-binding domain and the second target-binding domain each comprise a sequence that is at least 90% identical to SEQ ID NO: 85. The dependent claims state that the first target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 85; the soluble tissue factor domain comprises a sequence that is at least 90% identical to SEQ ID NO: 1; and the first domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 14; the second target-binding domain comprises a sequence that is at least 90% identical to SEQ ID NO: 85; and the second domain of the pair of affinity domains comprises a sequence that is at least 90% identical to SEQ ID NO: 28. The dependent claims state the first target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 85; the soluble tissue factor domain comprises a sequence that is at least 95% identical to SEQ ID NO: 1; and the first domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 14; the second target-binding domain comprises a sequence that is at least 95% identical to SEQ ID NO: 85; and the second domain of the pair of affinity domains comprises a sequence that is at least 95% identical to SEQ ID NO: 28. The dependent claims state that the first chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 133; and the second chimeric polypeptide comprises a sequence that is at least 90% identical to SEQ ID NO: 177. The dependent claims state that the first chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 133; and the second chimeric polypeptide comprises a sequence that is at least 95% identical to SEQ ID NO: 177. 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 genus of multichain chimeric polypeptide for treating an infectious disease, 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 broadly encompass treating any infectious disease with a vast genus of multichain chimeric polypeptides. Although the claims are inclusive of a multichain chimeric polypeptide comprising a first chimeric polypeptide comprising SEQ ID NO: 133, and a second chimeric polypeptide comprising SEQ ID NO: 177, 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: 133 or 177. The claims also recite the component parts of the chimeric polypeptide. Although the first and second target-binding domain claims are inclusive of each of SEQ ID NOs: 85, the soluble tissue factor is inclusive of SEQ ID NO:1, the first domain of the pair of affinity domain comprises SEQ ID NO: 14 and the second domain of the pair of affinity domain comprises SEQ ID NO: 28, 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: 85, 1, 14,and 28. This would represent a large pool of variant polypeptides that must have similar functional activity. A variance of 10%, for example, in the polypeptide set forth in SEQ ID NO: 85 that is 287 amino acids in length translates into 28 residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 287 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 90%. Applicants have not described which domain or portions of SEQ ID NOs: 85, 1, 14, 28, 133, or 177 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. 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).
Regarding the infectious disease, the specification establishes the breadth of the claims by teaching that 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. Therefore, there are hundreds of, of diseases and disorders encompassed. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The encompassed disorders are highly heterogeneous at both the molecular and clinical level. Here are some assorted examples:
Diseases that occur as a result of infections with virus, bacteria, fungus, or other pathogens generate inflammatory disorder symptoms such as skin rashes, fever, chills, fatigue, loss of energy, headaches, loss of appetite, muscle stiffness, insomnia, itchiness, stuffy nose, sneezing, and coughing. There are millions of possible infections that may be encompassed. Bacterial infection examples with inflammatory symptoms include Escherichia coli and Salmonella cause food poisoning, Helicobacter pylori causing gastritis and ulcers, Neisseria meningitidis causing meningitis, Staphylococcus aureus causing a variety of infections in the body, including boils, cellulitis, abscesses, wound infections, toxic shock syndrome, pneumonia, and food poisoning, and Streptococcal bacteria cause a variety of infections in the body, including pneumonia, meningitis, ear infections, and strep throat. Viral infections can include, for example, chickenpox, influenza, herpes, infectious mononucleosis, mumps, measles, rubella, viral gastroenteritis (stomach flu), viral hepatitis, viral meningitis, and viral pneumonia,
(5) The state of the prior art and (7) The predictability or unpredictability of the art
While the state of the art is relatively high with regard to the treatment of specific infections, the state with regard to treating these diseases broadly with a specific agent is under developed. In particular, there is no known agent that is effective to treat all infections. The infection disease treatment art involves a very high level of unpredictability.
The claims encompass a vast genus of multichain chimeric polypeptides having different chemical and physical properties. 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): 30-36), 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 an agent to meet the claimed functional limitations, including modulating the activity of TGFRβII and IL-15, being administered to a subject, and conferring therapeutic benefit to a subject with an infectious disease, 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 agent would be able to perform the functions in the claimed method.
Regarding viral infections, one of ordinary skill in the art knows that these viruses are quite diverse. Viruses exhibit huge variations in their nature. Some virions consist of just a capsid, some of just a nucleocapsid. Some consists of an envelope and a nucleocapsid, and some of an envelope and a core. Some virions consist of an envelope, a nucleocapsid, and a nucleoid. Other virions consist of an envelope, a matrix protein, a nucleoprotein complex, a nucleocapsid, and a polymerase complex, and there are many other forms as well. Broad based antivirals are unknown. Even an anti-viral agent against a family such as the Arenaviridae or the Bunyaviridae is unknown; these viruses are simply too diverse. The vast majority of RNA and DNA viruses have no effective antiviral treatment. It is the great diversity of the tern “viral infection” that makes practicing the claimed invention with regards to this genus of diseases unpredictable.
The state of the art regarding TGFβ1 in infections and infectious diseases is discussed by Reed (Microbes and Infection, 1, 1999, 1313−1325). Reed teaches that transforming growth factor-beta (TGF-β) has been analyzed for its role in regulating immune responses to a variety of pathogens, including viruses, bacteria, yeast, and protozoa (See page 1313). Reed teaches that some investigations have found that TGF-β has a negative influence on host responses and a beneficial effect on the survival and growth of intracellular pathogens. However, other studies have found that TGF-β may have a positive or beneficial effect in some models of infection (See page 1313). For instance, the presence of TGFβ favors virulence in Trypanosoma and Leishmania infections, whereas conflicting data have been generated in studies of macrophage-HIV interactions, and results obtained with some eukaryotic organisms have indicated that TGF-β does not play a purely negative role in the resistance to pathogens (See pages 1313-1314 and 1320). Reed teaches that it was found that in vitro treatment of macrophages with TGF-β impaired their ability to become activated by IFN-γ to limit intracellular growth of the yeast Candida albicans, yet administration of rTGF-β to susceptible mice had a protective effect as demonstrated by delayed progression of disease, along with lowered IL-4 production (See page 1321). Reed teaches that other beneficial effects of TGF-β in infectious diseases include decreasing arthritis resulting from exposure to streptococcal cell walls (See page 1322).
Moreover, protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in 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.
(6) The amount of direction or guidance by the inventor; (7) The existence of working examples
The specification teaches a fusion complex comprising TGFβ Receptor II/IL-15RαSu and TGFβ Receptor II/TF/IL-15. The specification teaches that the activity of TGFαRII in TGFRt15-TGFRs was evaluated by analyzing the effect of TGFRt15-TGFRs on the activity of TGFβ1 in HEK-Blue TGFβ cells. The specification teaches that the TGFβRII domain in TGFRt15-TGFRs was able to block the activity of TGFβ1 in HEK-Blue TGFβ cells. The specification teaches that to evaluate the activity of IL-15 in TGFRt15-TGFRs, the IL-15 activity of TGFRt15-TGFRs was compared to recombinant IL-15 using 32Dβ cells that express IL2Rβ and common γ chain, and evaluating their effects on promoting cell proliferation. The specification teaches TGFRt15-TGFRs and IL-15 promoted 32Dβ cell proliferation. The specification teaches wild type mice were treated subcutaneously with TGFRt15-TGFRs at a dosage of 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg. The specification teaches that in the spleens of mice treated with TGFRt15-TGFRs, the percentages of CD8+ T cells and NK cells both increased with increasing dosage of TGFRt15-TGFRs. The specification teaches that TGFRt15-TGFRs is able to stimulate immune cells in the spleen, in particular CD8+ T cells and NK cells. The specification teaches that splenocytes from TGFRt15-TGFRs-treated mice had stronger cytotoxicity against Yac-1 cells than the control mouse splenocytes. The specification teaches that animals receiving a combination of chemotherapy and TGFRt15-TGFRs had significantly smaller tumors comparing to the PBS group, whereas neither chemotherapy nor TGFRt15-TGFRs therapy alone work as sufficiently as the combination. It should be noted that the specification does not disclose any working example of treating an infectious disease with the claimed multichain chimeric polypeptide.
(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, limited to a statistical analysis of data from “infectious” vs. “healthy” subjects, without identifying the infections per se, to all of the specific infections and subjects encompassed, as broadly claimed. The skilled artisan simply cannot envision the specific infections 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 infections 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 infections in which subjects would have a lower concentration of TRAIL 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 infections and/or 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). It is noted that providing methods for determining which infections and subjects are included, would not reduce the amount of experimentation required because each must be determined empirically. 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.
Claim Status
No claims are allowed.
Conclusion
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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