DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/17/25 has been entered.
Claims 1, 16, 34, 39, 57, 67, 70, and 73 have been amended. Claims 2-15, 17-33, 35-38, 40-56, 58-66, 69, and 72 have been canceled. Claims 1, 16, 34, 39, 57, 67, 68, 70, 71, and 73-74 are pending and under examination.
Withdrawn Rejections
The rejection of claims 1, 16, 34, 39, 57 and 66-74 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), the second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to a pre -AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in light of Applicant’s amendment thereto. See paragraph 8, page 14 of the previous Office action.
The rejection of claims 1 under 35 U.S.C. 102(a)(1) as being anticipated by Jirakrit et al. (PLOS One, August 2, 2016), is withdrawn in light of Applicant’s amendment thereto. See paragraph 9, page 15 of the previous Office action.
The rejection of claims 1 and 66 under 35 U.S.C. 102(a)(1) as being anticipated by Zhou et al. (Nature 2020 July; 583(7817): 609-614), is withdrawn in light of Applicant’s amendment thereto. See paragraph 10, page 16 of the previous Office action.
Maintained Rejection
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 16, 34, 39, 57, 70, 71, 73, and 74 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 broadly encompass a genus of monovalent Fc fusion proteins comprising the IL-18 variants, and Fab-Fc fusion proteins that are not adequately described.
With regard to the Fc portion of the fusion proteins, the claims do not specify any particular Fc domain, and encompass any known Fc domain in the art. The specification teaches that “Fc” or “Fc region” or “Fc domain” refers to the polypeptide comprising the constant region of an antibody, in some instances, excluding all of the first constant region immunoglobulin domain (e.g., CH1) or a portion thereof, and in some cases, optionally including all or part of the hinge. The specification teaches that for IgG, the Fc domain comprises immunoglobulin domains CH2 and CH3 (Cy2 and Cy3), and optionally all or a portion of the hinge region between CH1 (Cγ1) and CH2 (Cy2). The specification teaches that in some cases, the Fc domain includes, from N- to C-terminus, CH2-CH3 and hinge-CH2-CH3. The specification teaches that in some embodiments, the Fc domain is that from IgG1, IgG2, IgG3 or IgG4, with IgG1 hinge-CH2-CH3 and IgG4 hinge-CH2-CH3 finding particular use in many embodiments. The specification teaches that wherein the Fc domain is a human IgG1 Fc domain, the hinge includes a C220S amino acid substitution. The specification teaches that in some embodiments where the Fc domain is a human IgG4 Fc domain, the hinge includes a S228P amino acid substitution. Thus, the claims broadly encompass IL-18 fusion proteins comprising any number of IL-18 variants and any number of Fc domains. Although, the specification describes specific fusion proteins comprising specific Fc domains, the claims encompass far more than the few species disclosed. Thus, the Fc fusion proteins are described only in terms of their function, and the specification fails to disclose a structure function correlation for the fusion proteins.
With regard to the Fab-Fc fusion proteins, the claims do not specify the structure of the variable chain, first Fc domain, variable light chain, or second Fc domain. The heavy and light chain must form an antigen binding fragment; however, there is no guidance regarding the heavy and light chain sequence such that one would know which heavy and light chains pair to form a functional antigen binding fragment. Thus, the Fab-Fc fusions are described only in terms of their function, and the specification fails to disclose a structure function correlation for the fusion proteins. These proteins have no correlation between their structure and function.
Furthermore, Application has not shown possession of a represented number of species that have the claimed function(s). While the specification sets forth a correlation between the IL-18 variants and fusion proteins comprising the variants specifically described in the specification, this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed Il-18 variants and IL-18 fusion protein sequences disclosed, and broadly encompass IL-18 variants with modifications at up to 75 positions, and in some embodiments, IL-18 variants comprising one or more modifications at any amino acid residue of the parent sequence. Further, the Fc fusions encompass any number of Fc domains, and the Fab-Fc fusions encompass any heavy chain and light chain variable region that forms an antigen binding site. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a few species have been described and this is not considered to be representative of the breadth of the genus.
There are substantial variations with species correlation, because of the numerous alternative species, and there is limited description of the species. While the specification clearly sets forth a correlation between variant IL-18 fusion proteins specifically disclosed by sequence in the specification, this correlation does not appear to be clearly present in the breadth of the claims. The claims are not limited to the disclosed variant IL18 fusion protein sequences and broadly encompass IL18 variants fused to anu number of IgG Fc domains and Fab portions. However, the genus of variants IL18 fusion proteins has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure of each species, in common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a few species have been described and this is not considered to be a representative number of species in the breadth of the genus. Therefore, the specification provides insufficient written description to support the genus encompassed by the claims.
MPEP §2163 states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance (as in the instant case), the disclosure must describe a sufficient variety of species to reflect the variation within that genus. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number to adequately describe a broad genus. The courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus (e.g., see In re Gostelli, 872, F. 2d at 1012, 10 USPQ2d at 1618).
Further, the disclosure of only one or two 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 genu[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). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when… the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Accordingly, the specification also does not provide adequate written description to identify the broad genus of the claimed, claimed only be a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous heterodimers had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of heterodimers claimed only by a partial structure and functional characteristic(s).
Vas-Cath Inc. v. Mahurkar, 19 U5PQ2d 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 fully described variant IL18 fusion proteins set forth in the specification, 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.
`University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d
1565,1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("The 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.
In Ariad Pharrns., Inc. v. Eh Lilly & Co., 598 F.3d 1336,1351 (Fed. Cir. 2010), the court held that a “sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize’ the members of the genus." Ariad, 598 F. Bd at 1350.
An adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials,” Id. Although “functional claim language can meet the written description requirement when the art has established a correlation between structure and function," "merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genu and showing that one has invented a genus and not just a species.”Id.
Tsutsumi et al. (“The structural for receptor recognition of the human interlukin-18. Nat Commun 5, 5340 p 2-4, Figure 2, Figure 3 (2014)) teach IL18, a proinflammatory cytokine which is secreted by various types of cells and strongly augments IFN-y production in type-1 helper T (Th1) cells and natural killer (NK) cells following activation of NK cell cytotoxicity. Tsutsumi et al. teaches the structures and associated biochemical and cellular data should aid in developing novel drugs (Tsutsumi et al See p 2).
Ring et al. (US2021/0015891 A1 publication date 21 January 2021) teach the various structural additions of one or more modifications, will have a more complex functional / structural, certain positions on sequences are critical for structural / functional relationship. The position in the protein’s sequence where such modifications and/or amino acid substitutions can be made with reasonable expectation of maintaining function in the claim, all the substitutions in the claims and modifications in the specification teaches, will be convoluted. (Ring et al, See paragraph [0071]).
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. Bowie et al. (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al. further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three-dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). 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 residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252,1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, 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 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 falls. 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). Given not only the teachings of Bowie et al., Lazar et al. and Burgess et al. but also the limitations and pitfalls of assigning a function to an amino acid sequence based upon similarity as taught by Whisstock, the claimed proteins could not be predicted. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the agent per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
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.” Lizardtech 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 genus. 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). In view of all of the above, the rejection is maintained.
Applicant’s Arguments
Applicant argues that the claims have been amended to recite an IL-18 variant protein comprising specific amino acid substitutions.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive. Although the claims have been amended to recite specific substitutions for the IL-18 variant, the claims still encompass a genus of fusion proteins that are not adequately described. The genus of fusion proteins is extremely broad because the claims recite generic and incompletely described fusion proteins. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed fusion proteins without adequate descriptions of its component parts or overall makeup. The generically claimed first Fc domain of human IgG, second domain of human IgG, and variable heavy and light chain 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 fusion proteins recited in the claims. For instance, without knowing the structure of the claimed variable heavy chain and variable light chain, one would not be able to adequately describe the claimed Fab portion of the fusion protein. Stating that the Fab comprises a variable heavy chain and a variable light chain is not a description of those specific components of the Fab. Thus, the claims identity the fusion proteins by their function and/or partial structure. 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 agent may generically describe the agent’s function, it does not describe the agent itself. A definition by function does not suffice to define the genus because it is only an indication of what the agent 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 agents is highly variable (i.e., each fusion polypeptide would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed fusion proteins have no correlation between their structure and function and the specification fails to provide adequate written description to support the genus of fusion polypeptides encompassed by the claims.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 34 and 57 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 34 and 57 reference amino acid substitutions (i.e., C220S/PVA_/S267K/L368D/K370S/M428L/N434S and PVA_/S267K/S364K/E357Q/M428L/N434S) that are designated at specific amino acid residues within a parent polypeptide. However, the claims do not provide a parent polypeptide, and therefore, it is impossible to determine where these substitutions would occur. Without a parent polypeptide, there is no way to identify the correct residue for substitution, determine whether the parent polypeptide has the required base amino acid, and confirm that the mutated polypeptide has the appropriate substituted amino acid. Therefore, there is ambiguity to the scope of the claims, and one of skill in the art would not be apprised of the metes and bounds of the claim. Clarification and/or correction is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Dinarello et al. (US Patent Application Number 20020169291, published November 15, 2002).
The instant claims are drawn to a composition comprising a variant human IL 18 protein, wherein the variant human IL18 protein comprises an amino acid substitution(s) selected from the group consisting of E6A, E6Q,S10C/E31Q/I49C, L15C/E31Q/R147C, P28C/E31Q/L136C, E31Q/S50C/P88C, E31Q/T63C/P88C, E31Q/V62C/Q103C, S10C/E31Q/N155C, E31Q/S65C/P88C, S7C/E31Q/S50C, E31Q/D54C/A61C, E31Q/A126C/K139C, N14W/E31Q, E31Q/D146Y, E31Q/D146L, E31Q/D146F, E31Q/M15OF, Q18L/E31Q, S7P/E31Q, V11I/E31Q, D23N/E31Q, D23S/E31Q, R27Q/E31Q, L29V/E31Q, E31Q/R39T, E31Q/R39S, E31Q/R44Q, E31Q/I46V,E31Q/S50Y, E31Q/K67Q, E31Q/E69K, E31Q/I71M, E31Q/I80T, E31Q/I81V, E31Q/I81L,E310/N87S, E310/D90E, E310/K93D/T95E, E310/K93N/T95E, E310/T95E, E310/K96G, E31Q/S97N, E31Q/S119L, E31Q/L144N, E31Q/R147K, E31Q/I149V, E31Q/M150T,E31Q/E156Q/D157N, D23N/E31Q/R27Q, E31Q/Q56L/T95E, E31Q/K96Q/S119L, E31Q/E141K/I149V, E31Q/E141Q/I149V, S7P/E31Q/S50Y, S10C/D35E/N155C, S10C/S36D/N155C, S10C/S36N/N155C, S10C/K53V/N155C, S10C/K53Y/N155C, S10C/K53F/N155C, S10C/M51R/N155C, S10C/M51L/N155C, S10C/M51H/N155C, S10C/M51F/N155C, S10C/M51Y/N155C, S10C/S55D/N155C, S10C/S55E/N155C, S10C/S55T/N155C, S10C/P57Q/N155C, S10C/P57D/N155C, S10C/P57Y/N155C, S10C/P57N/N155C, S10C/M60Y/N155C, S10C/M60F/N155C, S10C/D110Q/N155C, S10C/D110R/N155C, S10C/N111D/N155C, S10C/N111S/N155C, S10C/N111T/N155C, S10C/N111E/N155C, S10C/D132Q/N155C, S10C/D132E/N155C, E6Q/S10C/K53D/N155C, E6Q/S10C/M51K/K53D/N155C, S10C/E31Q/D35N/N41Q/K53A/N155C, S10C/E31Q/N41Q/K53A/N155C, S10C/E31Q/K53A/N155C, S10C/K53T/N155C, S10C/P57A/N155C, S10C/N155C, S10C/K53D/N155C, S10C/E31Q/N41Q/N155C, S10C/M51L/K53D/N155C, S10C/K53D/D110R/N155C, S10C/K53D/N111T/N155C, S10C/K53D/S55T/N155C, S10C/K53D/S55T/D110R/N155C, S10C/M51L/K53D/S55T/D110R/N111T/N155C, S10C/M51L/K53D/S55T/D110R/N155C, S10C/K53D/S55T/D110R/N111T/N155C, S10C/K53D/S55T/N111T/N155C, S10C/E31Q/D35N/N155C, S10C/N41Q/N155C, S10C/D35N/N155C, S10C/D37N/N155C, S10C/E31Q/D37N/N155C, S10C/D35N/D37N/N155C, S10C/D37N/K53D/N155C, and E6Q/S10C/K53D/N111T/N155C, as compared to wildtype human 1L18 of SEQ IDNO: 1 or SEQ ID NO: 2.
Dinerello et al. teach an IL-18 mutant comprising the E6A substitution, which has the amino acid sequence set forth in SEQ ID NO: 6 (See paragraph 0020). Thus, Dinerello et al. anticipate the claims.
<210> SEQ ID NO 6
<211> LENGTH: 157
<212> TYPE: PRT
<213> ORGANISM: Artificial Sequence
<220> FEATURE:
<223> OTHER INFORMATION: Synthetic PRT Sequence
<400> SEQUENCE: 6
Tyr Phe Gly Lys Leu Ala Ser Lys Leu Ser Val Ile Arg Asn Leu Asn
1 5 10 15
Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp
20 25 30
Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile
35 40 45
Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile
50 55 60
Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile
65 70 75 80
Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys
85 90 95
Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys
100 105 110
Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu
115 120 125
Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu
130 135 140
Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp
145 150 155
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1 and 67 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dinarello et al. (US Patent Application Number 20020169291, published November 15, 2002) in view of Kato et al. (WO 2005/075648 A1, published August 18, 2005).
The instant claims are drawn to a composition comprising a variant human IL 18 protein, wherein the variant human IL18 protein comprises an amino acid substitution(s) selected from the group consisting of E6A, E6Q,S10C/E31Q/I49C, L15C/E31Q/R147C, P28C/E31Q/L136C, E31Q/S50C/P88C, E31Q/T63C/P88C, E31Q/V62C/Q103C, S10C/E31Q/N155C, E31Q/S65C/P88C, S7C/E31Q/S50C, E31Q/D54C/A61C, E31Q/A126C/K139C, N14W/E31Q, E31Q/D146Y, E31Q/D146L, E31Q/D146F, E31Q/M15OF, Q18L/E31Q, S7P/E31Q, V11I/E31Q, D23N/E31Q, D23S/E31Q, R27Q/E31Q, L29V/E31Q, E31Q/R39T, E31Q/R39S, E31Q/R44Q, E31Q/I46V,E31Q/S50Y, E31Q/K67Q, E31Q/E69K, E31Q/I71M, E31Q/I80T, E31Q/I81V, E31Q/I81L,E310/N87S, E310/D90E, E310/K93D/T95E, E310/K93N/T95E, E310/T95E, E310/K96G, E31Q/S97N, E31Q/S119L, E31Q/L144N, E31Q/R147K, E31Q/I149V, E31Q/M150T,E31Q/E156Q/D157N, D23N/E31Q/R27Q, E31Q/Q56L/T95E, E31Q/K96Q/S119L, E31Q/E141K/I149V, E31Q/E141Q/I149V, S7P/E31Q/S50Y, S10C/D35E/N155C, S10C/S36D/N155C, S10C/S36N/N155C, S10C/K53V/N155C, S10C/K53Y/N155C, S10C/K53F/N155C, S10C/M51R/N155C, S10C/M51L/N155C, S10C/M51H/N155C, S10C/M51F/N155C, S10C/M51Y/N155C, S10C/S55D/N155C, S10C/S55E/N155C, S10C/S55T/N155C, S10C/P57Q/N155C, S10C/P57D/N155C, S10C/P57Y/N155C, S10C/P57N/N155C, S10C/M60Y/N155C, S10C/M60F/N155C, S10C/D110Q/N155C, S10C/D110R/N155C, S10C/N111D/N155C, S10C/N111S/N155C, S10C/N111T/N155C, S10C/N111E/N155C, S10C/D132Q/N155C, S10C/D132E/N155C, E6Q/S10C/K53D/N155C, E6Q/S10C/M51K/K53D/N155C, S10C/E31Q/D35N/N41Q/K53A/N155C, S10C/E31Q/N41Q/K53A/N155C, S10C/E31Q/K53A/N155C, S10C/K53T/N155C, S10C/P57A/N155C, S10C/N155C, S10C/K53D/N155C, S10C/E31Q/N41Q/N155C, S10C/M51L/K53D/N155C, S10C/K53D/D110R/N155C, S10C/K53D/N111T/N155C, S10C/K53D/S55T/N155C, S10C/K53D/S55T/D110R/N155C, S10C/M51L/K53D/S55T/D110R/N111T/N155C, S10C/M51L/K53D/S55T/D110R/N155C, S10C/K53D/S55T/D110R/N111T/N155C, S10C/K53D/S55T/N111T/N155C, S10C/E31Q/D35N/N155C, S10C/N41Q/N155C, S10C/D35N/N155C, S10C/D37N/N155C, S10C/E31Q/D37N/N155C, S10C/D35N/D37N/N155C, S10C/D37N/K53D/N155C, and E6Q/S10C/K53D/N111T/N155C, as compared to wildtype human 1L18 of SEQ IDNO: 1 or SEQ ID NO: 2.
Dinerello et al. teach an IL-18 mutant comprising the E6A substitution, which has the amino acid sequence set forth in SEQ ID NO: 6 (See paragraph 0020).
<210> SEQ ID NO 6
<211> LENGTH: 157
<212> TYPE: PRT
<213> ORGANISM: Artificial Sequence
<220> FEATURE:
<223> OTHER INFORMATION: Synthetic PRT Sequence
<400> SEQUENCE: 6
Tyr Phe Gly Lys Leu Ala Ser Lys Leu Ser Val Ile Arg Asn Leu Asn
1 5 10 15
Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp
20 25 30
Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile
35 40 45
Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile
50 55 60
Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile
65 70 75 80
Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys
85 90 95
Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys
100 105 110
Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu
115 120 125
Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu
130 135 140
Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp
145 150 155
Dinerello et al. do not teach wherein the variant human IL-18 protein comprises the 4CS/E6A substitution.
Kato et al. teach an IL-18 variant in which the cysteines at positions 38, 68, 76, and 127 are each substituted with a serine (See pages 3 and 9.) Kato et al. teach that the mutant is highly stable, and does not form oligomers, and shows no decrease in biological activities (See page 3).
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the IL-18 variant of Dinerello et al. to additionally include the 4CS substitutions, as taught by Kato et al., because Kato et al. teach that substituting the cysteines residues increases the stability of the IL-18 protein, without affecting its biological activity. One of ordinary skill in the art would be motivated to generate an IL-18 variant comprising the E6A and 4CS substitutions because doing so would provide an IL-18 protein that is highly stable and retains biological activity when applied for therapeutic purposes.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". The combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claim Status
Claim 68 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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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