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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-9, 14-17, 22-23) in the reply filed on 9/15/2025 is acknowledged.
In response to an interview with the Examiner on 9/26/2025, Applicant’s representative Sangil Lee submitted amended claims 1, 4, 8, 14, 22-23, (10/17/2025), and previously presented claims 2-3, 9, 15.
Claims 7, 10-13, 16-21, and 24-30 have been canceled.
Information Disclosure Statement
3. The information disclosure statements (IDS) submitted on 3/14/2025, 1/4/2023, and 12/7/2022, are in compliance with the provisions of 37 CFR 1.97 and have been considered by the examiner.
Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section”.
Claim Rejections - 35 USC § 112(a), lack of written description
4. 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.
4a. Claims 1-6, 8-9, 14-15, and 22-23 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Independent claim 1 is drawn to “an IL-10 mutein, wherein the IL-10 mutein comprises at least one amino acid substitution at positions 18, 92 and 99, as compared to full-length wild-type IL-10 (SEQ ID NO: 1), wherein numbering is with respect to the wild-type IL- 10 sequence found shown in SEQ ID NO: 1, but excluding the signal peptide sequence which constitutes the first 18 amino acid residues in SEQ ID NO: 1.”
Dependent claim 2 is drawn to “the IL-10 mutein according to claim 1, wherein the IL-10 mutein comprises at least two amino acid substitutions at positions 18, 92 and 99.”
Furthermore, dependent claim 3 is drawn to “the IL-10 mutein according to claim 1, wherein the IL10 mutein comprises amino acid substitutions at all three positions, 18, 92 and 99.”
Additionally, claim 9 is drawn to “the IL-10 mutein according to claim 1, wherein the IL-10 mutein is at least 97, 98, 99% or 100% identical to the sequence according to SEQ ID NO:5, 7, 11 or 15, but comprises at least the amino acid substitutions identified in SEQ ID NO:5, 7, 11 or 15, which differ with respect to the corresponding wild-type IL-10 sequence (SEQ ID NO: 1).”
Claim 22 is drawn to “the IL-10 mutein according to claim 1, wherein the IL-10 mutein binds to IL-10Rβ with a Kd which is 100-fold lower compared to the binding of wild type IL-10 to IL-10Rβ.”
The claims as recited would represent a large pool of variant IL-10 polypeptides that must have similar functional desired activity as recited in claim 22. A 97% variance (in claim 9), in SEQ ID NO:5, 7, 11, or 15 that are 178 amino acids in length translates into 5.3% of the amino acid residues that may be substituted, added or deleted, anywhere throughout the entire length of the polypeptide comprising 178 amino acids. There is no limit in the claim, as recited, that the variance be contiguous. Moreover, there is no limitation stating that a substitution in claim 1, for example, be a conservative substitution. As a result, there are potentially thousands of variant permutations that could be made. Applicants have not described which portions of SEQ ID NO: 1 are critical to the function of the protein. The specification provides limited guidance regarding which amino acids can be modified in the genus of proteins, while maintaining the desired given function. Therefore, these structures (i.e., sequence variants) are claimed only by 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 claimed IL-10 muteins is broad and one of ordinary skill in the art would not be reasonably apprised of the structure of the claimed muteins without adequate description of its component parts or overall makeup. The claims as recited do not impart enough structural information to permit one of ordinary skill in the art to reasonably recognize or understand that Applicants were in possession of the full scope of the genus of variant IL-10 proteins recited in the claims.
The invention contemplates IL-10 polypeptide variants of, for example, substitution at least one of positions 18, 92, and 99, as recited in claim 1. The specification does not provide adequate written description to identify the broad and variable genus of proteins because, inter alia, the specification does not disclose a correlation between the necessary structure of the protein and the function(s) of the protein; and thus, the specification does not distinguish the claimed genus from others. Accordingly, the specification does not define any structural features commonly possessed by members of the genus of variant IL-10 polypeptides. In addition, because the genus of claimed polypeptide is highly variable (i.e., each variant polypeptide would necessarily have a unique structure; see MPEP 2434), the generic description of the variant IL-10 polypeptide is insufficient to describe the genus.
Further, Applicants have not shown possession of a representative number of species of the claimed proteins. As noted above, the claims are generic for IL-10 proteins recited in claim 1. 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.)
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, 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 (page 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 (page 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (page 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (page 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 (page 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 (page 400, paragraph bridging columns 1 and 2).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g., alanine) in a sequence, results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e., each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Bowie et al., Lazar et al., Burgess et al., and Greenspan 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 polypeptides could not be predicted as claimed.
Applicants have provided little or no descriptive support beyond the mere presentation of function in claim 22 to enable one of ordinary skill in the art to determine the actual structural composition of the claimed genus of IL-10 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 IL-10 proteins to Applicants. 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 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 Applicants were in possession of the genus of IL-10 muteins as claimed.
For the reasons set forth above, Applicants have failed to describe “an IL-10 mutein, wherein the IL-10 mutein comprises at least one amino acid substitution at positions 18, 92 and 99, as compared to full-length wild-type IL-10 (SEQ ID NO: 1), wherein numbering is with respect to the wild-type IL- 10 sequence found shown in SEQ ID NO: 1, but excluding the signal peptide sequence which constitutes the first 18 amino acid residues in SEQ ID NO: 1”, as recited in claim 1.
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 Applicants were in possession of the claimed IL-10 muteins. 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).
Therefore, the claims fail to meet the written description provision of 35 U.S.C. §112(a). In the instant case, Applicants have failed to describe which variant IL-10 muteins have the desired properties claimed.
Claim Rejections - 35 U.S.C. § 112(b)
5. 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.
5a. Claim 8 is 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 pre-AIA the applicant regards as the invention.
Claim 8 is rejected as vague and indefinite for several reasons.
Claim 8 recites the limitation "wherein said one or more further substitutions" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Furthermore, it is unclear if the substitutions recited in claim 8, are in SEQ ID NO:1, but excluding the signal peptide sequence which constitutes the first 18 amino acid residues in SEQ ID NO:1.
Claim rejections-35 USC § 112(d)
6. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
6a. Claim 9 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 9 recites the limitation “the IL-10 mutein according to claim 1, wherein the IL-10 mutein is at least 97, 98, 99% or 100% identical to the sequence according to SEQ ID NO:5, 7, 11 or 15, but comprises at least the amino acid substitutions identified in SEQ ID NO:5, 7, 11 or 15, which differ with respect to the corresponding wild-type IL-10 sequence (SEQ ID NO: 1)” which is broader in scope than the limitation recited in claim 1, from which claim 9 depends. A dependent claim cannot be broader in scope than the claim from which it depends. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
NOTE: Claim 1 has been interpreted by the Examiner as an IL-10 mutein comprising substitutions in SEQ ID NO:1 (178 amino acids) at positions 36 (Asn), 110 (Asn), and 117 (Lys), which correspond to positions at 18, 92, and 99 in SEQ ID NO:1, without the N-terminal 18 amino acid residues signal sequence in SEQ ID NO:1, the mature wild-type IL-10 sequence starting at Ser Pro Gly (See specification, page 2, last 3 lines; page 3, first 2 lines; page 3, lines 12-17).
Conclusion
No claim is allowed.
Claims 1-6, 8-9, 14-15, and 22-23, are rejected.
Advisory Information
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/PREMA M MERTZ/ Primary Examiner, Art Unit 1646