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 of Group I (1-2, 7, 13-14, 17, 19-20, 23, 38, 40, 56, 58, 61, 63, 65, 67, 75, 78, 82, 85-87, 91-92, 96, 100, 142; species: the first amino acid sequence is SEQ ID NO:5; the second amino acid sequence is SEQ ID NO:357; the third amino acid sequence is SEQ ID NO:7; the fourth amino acid sequence is SEQ ID NO:74; the fifth amino acid sequence is SEQ ID NO:9; the sixth amino acid sequence is SEQ ID NO:5; the seventh amino acid sequence is SEQ ID NO:357; the eight amino acid sequence is SEQ ID NO:7; the ninth amino acid sequence is SEQ ID NO:74; the tenth amino acid sequence is SEQ ID NO:9) in the reply filed on 4/13/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 25, 30, 43, 48, 140-141, 143, 97-101 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 3-6, 8-12, 15-16, 18, 21-22, 24, 26-29, 31-37, 39, 41-42, 44-47, 49-55, 57, 59-60, 62, 64, 66, 68-74, 76-77, 79-81, 83-84, 88-90, 93-95, and 102-139, have been canceled.
Information Disclosure Statement
3. The information disclosure statements (IDS) submitted on 4/13/2026, 1/7/2026, 10/1/2025, 5/5/2025, and 1/29/2025 are in compliance with the provisions of 37 CFR 1.97 and has 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, first paragraph, 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 1-2, 7, 13-14, 17, 19-20, 23, 38, 40, 56, 58, 61, 63, 65, 67, 75, 78, 82, 85-87, 91-92, 96, 100, 142, 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 recites an amino acid sequence having at least 95% sequence identity with SEQ ID NO:5 (Fc), SEQ ID NO:7 (human IL-2), SEQ ID NO:9 (IL-2R) amino acid sequences. Dependent claim 2 is drawn to the peptide of claim 1 and wherein the Fc sequences are 95% identical to SEQ ID NO:11, 12, 13, or 14. The claims as recited would represent a large pool of variant peptides that must have similar functional activity. A 95% variance, for example, in the polypeptide set forth in SEQ ID NO: 7 that is 133 amino acids in length translates into 5% of the amino acid residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 133 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. Applicants have not described which portions of SEQ ID NO: 7 are critical to the function of the protein. The specification provides limited guidance regarding which amino acids can be modified in the genus of peptides, while maintaining any 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 peptides is extremely broad because the claims recite generic and incompletely described peptides. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed peptides without adequate descriptions 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 Applicant was in possession of the full scope of the genus of variant peptides recited in the claims.
The invention contemplates polypeptide variants characterized by having at least 95% sequence identity to any of the sequences with mutations as recited in claim 1. 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) of the polypeptide; 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 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 peptide is insufficient to describe the genus.
Further, Applicants have not shown possession of a representative number of species of the claimed polypeptides. As noted above, the claims are generic for the components of the polypeptide. 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 reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
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 cols 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 peptides could not be predicted as claimed.
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 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 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 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).
Therefore, the full breadth of the claims fails to meet the written description provision of 35 U.S.C. §112, first paragraph. In the instant case, for example, Applicants have failed to describe which “amino acid sequences having at least 95% sequence identity” to the polypeptide having SEQ ID NO: 5, 7, an 9, have the desired properties claimed.
Claim Rejections - 35 U.S.C. § 112 second paragraph
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. Claims 1-2, 7, 13-14, 17, 19-20, 23, 38, 40, 56, 58, 61, 63, 65, 67, 75, 78, 82, 85-87, 91-92, 96, 100, 142 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 pre-AIA the applicant regards as the invention.
Claim 1, lines 3, 7, 11, 14, 18, 22, is vague and indefinite because it recites “at least about 95% sequence identity” and it is unclear if this limitation encompasses “50%, 75% or 99% sequence identity”. The metes and bounds of the limitation are unclear.
Similarly, claims 2, and 7, are vague and indefinite because they recite the limitation “at least about 95% sequence identity”.
Claim 2 is vague and indefinite because it recites “wherein the second polypeptide comprises N-terminal to the first amino acid sequence” however, there is no first amino acid sequence in the second polypeptide.
Claim 40 is vague and indefinite because it recites “….the second amino acid sequence is 15 or fewer amino acid acids in length” and it is unclear what the lower limit of the limitation encompasses. Does it encompass a single amino acid? Furthermore, the second amino acid sequence is SEQ ID NO:357 which is 25 amino acids, so the second amino acid sequence can be 15, 10 or 5 amino acids.
Claim 58 is vague and indefinite because it recites “….the seventh amino acid sequence is 15 or fewer amino acid acids in length” and it is unclear what the lower limit of the limitation encompasses. Does it encompass a single amino acid? Furthermore, the seventh amino acid sequence is SEQ ID NO:357 which is 25 amino acids, so the seventh amino acid sequence can be 15, 10 or 5 amino acids.
Claim 86 is vague and indefinite because it recites the limitation “wherein the first polypeptide chain lacks additional sequences C-terminal to the first amino acid sequence” because C-terminal to the first amino acid sequence is the second, third, fourth, and fifth amino acid sequences. Appropriate correction of the claim is required to obviate this rejection.
Similarly claim 91 is vague and indefinite because it recites the limitation “wherein the second polypeptide chain lacks additional sequences C-terminal to the sixth amino acid sequence” because C-terminal to the sixth amino acid sequence is the seventh, eighth, ninth, and tenth amino acid sequences. Appropriate correction of the claim is required to obviate this rejection.
Claims 7, 13-14, 17, 19-20, 23, 38, 56, 61, 63, 65, 67, 75, 78, 82, 85, 87, 92, 96, 100, 142 are rejected as vague and indefinite insofar as they depend on the above rejected claims for their limitations.
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. Claims 17, 23, 63, 67, 78, 85 are 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 17 recites the limitation “the IL2 proprotein of claim 1, wherein the first amino acid sequence is 330 or fewer amino acids in length” which is broader in scope than the limitation recited in claim 1, from which claim 17 depends because claim 1 recites that the first amino acid of SEQ ID NO:5 is 228 amino acids in length. A dependent claim cannot be broader in scope than the claim from which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Similarly, claim 23 recites the limitation “the IL2 proprotein of claim 1, wherein the sixth amino acid sequence is 330 or fewer amino acids in length” which is broader in scope than the limitation recited in claim 1, from which claim 23 depends because claim 1 recites that the sixth amino acid of SEQ ID NO:5 is 228 amino acids in length.. A dependent claim cannot be broader in scope than the claim from which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 63 recites the limitation “the IL2 proprotein of claim 1, wherein the third amino acid sequence is 135 or fewer amino acids in length” which is broader in scope than the limitation recited in claim 1, from which claim 63 depends because claim 1 recites that the third amino acid of SEQ ID NO:7 is 133 amino acids in length. A dependent claim cannot be broader in scope than the claim from which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 67 recites the limitation “the IL2 proprotein of claim 1, wherein the eight amino acid sequence is 135 or fewer amino acids in length” which is broader in scope than the limitation recited in claim 1, from which claim 67 depends because claim 1 recites that the eighth amino acid of SEQ ID NO:7 is 133 amino acids in length. A dependent claim cannot be broader in scope than the claim from which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 78 recites the limitation “the IL2 proprotein of claim 1, wherein the fifth amino acid sequence is 170 or fewer amino acids in length” which is broader in scope than the limitation recited in claim 1, from which claim 78 depends because claim 1 recites that the fifth amino acid of SEQ ID NO:9 is 145 amino acids in length.. A dependent claim cannot be broader in scope than the claim from which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 85 recites the limitation “the IL2 proprotein of claim 1, wherein the tenth amino acid sequence is 170 or fewer amino acids in length” which is broader in scope than the limitation recited in claim 1, from which claim 85 depends because claim 1 recites that the tenth amino acid of SEQ ID NO:9 is 145 amino acids in length. A dependent claim cannot be broader in scope than the claim from which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
No claim is allowed.
Claims 1-2, 7, 13-14, 17, 19-20, 23, 38, 40, 56, 58, 61, 63, 65, 67, 75, 78, 82, 85-87, 91-92, 96, 100, and 142 are rejected.
Advisory Information
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/PREMA M MERTZ/ Primary Examiner, Art Unit 1674
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