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 .
Claim Status
Applicant’s amendments and remarks, filed 03/02/2026, are acknowledged.
Claims 2-3, 10-14, and 16-19 are canceled.
Claims 1, 4-6, 8-9, 15, 20-21, and 23-25 are amended.
Claims 26-29 are new.
Claims 1, 4-9, 15, and 20-29 are pending.
As such, claims 1, 4-9, 15, and 20-29 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Withdrawn Objections
The sequence disclosure objections are withdrawn. Issues regarding missing the incorporation by reference paragraph and sequences appearing in the specification not identified by sequence identifiers have been sufficiently addressed through amendments to the specification on 03/02/2026.
The specification objections are withdrawn. Issues regarding minor informalities and trademarks/names have been sufficiently addressed through amendments to the specification and abstract on 03/02/2026.
The claim objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the claims filed on 03/02/2026.
Withdrawn Rejections
Applicant’s arguments, see pages 10 and 11, filed 03/02/2026, with respect to claims 1, 4-9, 15, and 20-25 rejected under 35 USC 112(b) as allegedly being indefinite have been fully considered and are persuasive. The issue regarding the claims comprising indefinite language have been sufficiently addressed through amendments to the claims. As such, the rejection under 35 USC 112(b) is withdrawn.
The rejection of claims 1, 4-9, 15, and 20-25 under 35 USC 112(a) as allegedly failing to comply with the written description requirement is modified in favor of the new limitations added in the amendment filed 03/02/2026. Specifically, Examiner acknowledges that claims 1 and 4 were amended to recite “consisting of” and “consists of” in place of “as shown in” for the recited sequences. Applicant’s arguments, see page 11, filed 03/02/2026, with respect to claims 1, 4-9, 15, and 20-25 rejected under 35 USC 112(a) have been fully considered.
The provisional double patenting rejection of claims 1, 4-9, 15, and 20-25 is modified in favor of the new limitations added in the amendment filed 03/02/2026. Specifically, Examiner acknowledges new claims 26-29. Applicant’s arguments, see page 11, filed 03/02/2026, with respect to claims 1, 4-9, 15, and 20-25 provisionally rejected under double patenting have been fully considered.
Maintained Rejections
Claim Rejections - 35 USC § 112(a) Written Description
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 5-9, 20, 22-25, and 28-29 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 5 is drawn to a protein, wherein the protein comprises domains of: (1) the IL-15 mutant polypeptide of claim 1; (2) an immunoglobulin molecule or part thereof fused to the IL-15 mutant polypeptide; and (3) subunits α of interleukin 15 receptor (IL-15Rα) fused to the IL-15 mutant polypeptide.
Claim 6 is drawn to the protein according to claim 5, wherein individual domains of the protein are connected from N-terminus to C-terminus in order of: an immunoglobulin molecule or a fragment crystallizable (Fc) region of the immunoglobulin molecule, the IL-15Rα, and the IL-15 mutant polypeptide wherein the IL-15Rα is fused to C-terminus of the fragment crystallizable region (Fc region) of the immunoglobulin molecule.
Claim 7 is drawn to the protein according to claim 5 comprising: (1) an immunoglobulin heavy chain; (2) an immunoglobulin light chain; (3) an IL-15Ra; and (4) the IL-15 mutant polypeptide of claim 1.
Claim 8 is drawn to the protein according to claim 5 comprising: (1) an Fc region of immunoglobulin; (2) an IL-15Rα; and, (3) the IL-15 mutant polypeptide of claim 1.
Claim 9 is drawn to the protein according to claim 5, wherein the immunoglobulin is an anti-programmed death-ligand 1 (PD-L1) antibody; and the IL-15Rα is IL-15Rα-sushi.
Claim 20 is drawn to the protein according to claim 5, wherein the immunoglobulin molecule is an antibody or an antigen-binding fragment, the antibody or antigen- binding fragment is: (1) a chimeric antibody or fragment thereof; or (2) a humanized antibody or fragment thereof.
Claim 22 is drawn to the protein according to claim 5, wherein the IL-15 mutant polypeptide is fused to the immunoglobulin molecule or part thereof with a linker peptide, or the IL-15 mutant polypeptide is fused to the IL-15Ra with a linker peptide.
Claim 23 is drawn to the protein according to claim 5, wherein the IL-15 mutant polypeptide is fused to the IL-15Ra with a linker peptide, and then fused to the immunoglobulin molecule or part thereof with a linker peptide.
Claim 24 is drawn to the protein according to claim 7, wherein the protein is a homodimer formed by dimerization of the Fc region of the immunoglobulin heavy chain.
Claim 25 is drawn to the protein according to claim 8, wherein the protein is a homodimer formed by dimerization of the Fc region.
Claim 28 is drawn to the protein according to claim 24, wherein the IL-15Rα is fused to C-terminus of the Fc region of the immunoglobulin heavy chain with a linker peptide; and the IL-15 mutant polypeptide is fused to C-terminus of the IL-15Ra with a linker peptide.
Claim 29 is drawn to the protein according to claim 25, wherein the IL-15Rα is fused to N-terminus of the IL-15 mutant polypeptide with a linker peptide, and the IL-15 mutant polypeptide fused to N-terminus of the immunoglobulin Fc region with a linker peptide.
The specification discloses of a murine PD-L1 antibody (PDL1-794) and a humanized PD-L1 antibody (794-h1-71), and their corresponding sequences (see Examples 1-3 and Tables 1-2). The 794-h1-71 antibody could effectively block the interaction between human PD-L1 protein and human PD-1 protein (see Examples 4-7). The 794-h1-71 antibody can also enhance T cell function in a dose-dependent manner (see Example 7).
The specification also discloses of PD-L1 and IL-15 fusion proteins, and the corresponding sequences (see Examples 8-11 and Tables 3-6). Specifically, the specification discloses that fusion proteins 794-IL15-com6-2 and V9-IL15-com6, comprising a mutant IL-15 comprising D8S and H105K mutations (SEQ ID NO: 45), exhibited a reduced effect on proliferative activity of CD8+ T cells and NK cells (see Examples 13 and 14, respectively). Further, the specification discloses that the 794-IL15-com6-2 group in the in vivo study had significant inhibitory effect on tumor volume compared to the Tecentriq group (see Example 15 and Tables 8-10).
However, the specification fails to disclose that Applicant was in possession of the large genus of proteins and pharmaceutical compositions as claimed. Specifically, the specification fails to disclose that Applicant was in possession of the large genus of immunoglobulin molecules or part thereof as recited in claims 5-7 and 20. Further, the specification fails to disclose that Applicant was in possession of the claimed protein comprising any anti-PD-L1 antibody.
Although the specification discloses of fusion proteins (see Tables 3 and 5), specifically 794-IL15-com6-2 and V9-IL15-com6, the claims are not limited to these proteins, and are inclusive of any immunoglobulin molecule or part thereof. This indicates that there are hundreds, if not thousands, of possible fusion proteins and pharmaceutical compositions encompassed by the claims. Thus, the claims encompass a vast genus of proteins that have the claimed functions. However, the specification provides limited guidance on the structure required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of fusion proteins and pharmaceutical compositions because, inter alia, the specification does not disclose a correlation between the necessary structure of the inhibitor and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies/anti-tumor agents and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of fusion proteins. 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 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).
The instant claims do not fully describe the structure of the immunoglobulin molecule to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of fusion proteins or pharmaceutical compositions, claimed only by 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 fusion proteins 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 fusion proteins claimed only by a partial structure and functional characteristic(s). Thus the fusion proteins described by the instant claims encompasses an overly broad genus, the structure of the immunoglobulin, and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of the function of the immunoglobulin molecule or part thereof. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
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.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed fusion proteins, 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 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 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.
Regarding the encompassed immunoglobulin molecules that are antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416; previously submitted with the Office Action mailed 12/01/2025) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2; previously submitted with the Office Action mailed 12/01/2025), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed immunoglobulin molecules that are proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9; previously submitted with the Office Action mailed 12/01/2025), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
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; previously submitted with the Office Action mailed 12/01/2025) 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; previously submitted with the Office Action mailed 12/01/2025) 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.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98; previously submitted with the Office Action mailed 12/01/2025) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400; previously submitted with the Office Action mailed 12/01/2025) 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).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668; previously submitted with the Office Action mailed 12/01/2025), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
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; previously submitted with the Office Action mailed 12/01/2025). 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 Skolnick 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 fusion proteins could not be predicted based on sequence identity. Clearly, it could not be predicted that a 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.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of proteins, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all fusion proteins and pharmaceutical compositions.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
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 fusion proteins. 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).
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 fusion proteins as claimed. 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).
Applicant’s Arguments
Applicant respectfully traverses the written description rejection (see page 11 of the Remarks filed 03/02/2026). As noted above, claims 1 and 4 are amended herein to recite "consisting of' and "consists of' in place of "as shown in" for the recited sequences. New claims 26 and 27 also recite "consisting of' for the recited sequences. Additionally, the IL-15 mutant protein, while not drug- like in its native form, exhibits superior functional effects when fused with Fc and antibody compared to the original antibody. This technical effect stems from the introduction of the IL-15 mutant. Therefore, as a single fusion protein fragment, the IL-15 mutant also possesses biological function. Furthermore, for the claimed fusion proteins, Examples 12-16 in the specification demonstrate the functionality of fusion proteins with typical structures as shown in Figures 5B and SD. Thus, the specification provides adequate description to convey that the Applicant had possession of the claimed subject matter.
Response to Arguments
Applicant's arguments filed 03/02/2026 have been fully considered but they are not persuasive. As stated above, Examiner acknowledges that claims 1 and 4 were amended to recite “consisting of” and “consists of” in place of “as shown in” for the recited sequences thus providing sufficient written description for the IL-15 mutant. However, the immunoglobulin recited in claims 5-8, 20, 22-25, and 28-29, and anti-PD-L1 antibody of claim 9 are solely described by their function and/or partial structure. While Applicant is entitled to use functional language in the description of claimed agents, according to MPEP 2163, an invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. This matches the facts here. The claims require specific functionality for the immunoglobulin molecule or antibody, but neither the instant disclosure, nor the art, provide description of the corresponding structure for that functionality or a representative number of species for the agents/components. For example, the immunoglobulins are defined by their ability to bind to a specific protein (i.e., PD-L1). In both the base claims and the dependent claims, for at least one agent/component in each claim, the claims only describe what the agent/component does, not what the agents/components are. Even when given possible sequences from which to select a fragment of an immunoglobulin, the question remains about which one(s) of the encompassed peptides would actually perform the claimed function. While methods to identify the peptides with the required function may be routine in the art, the fact that any experimentation is required to figure out exactly what is encompassed necessarily means that applicant has not sufficiently described the claimed subject matter.
There are thousands of possible immunoglobulin molecules encompassed by the instant claims. One of skill in the art could not immediately envisage the encompassed species in each genus from the guidance provided in the instant specification and claims. Applicant has supplied a single species of anti-PD-L1 antibodies (i.e., 794-h1-71). Further, the claims are not limited to this species, the claims encompass all immunoglobulin molecules or parts thereof. This encompasses an extremely broad genus of peptides with a specific function, for which no correlating structure is provided. While one of skill in the art could likely screen for said peptides and antibodies, the mere fact that experimentation is necessary to identify the members of the genus indicates that proper description has not been provided.
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005). Describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene' s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described.").
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 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. Further, arguments relating to the isolation of an antibody with specific characteristics may be more appropriately directed to the invention' s enablement, since the method of isolating would detail how to make the invention. However, the enablement of the invention has not been rejected by the Examiner.
As such, the written description rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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18/711,230
Claims 1, 4-9, 15, and 20-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-9, 11-13, 15, 17, 19-21, 23, and 26-27 of copending Application No. 18/711,230.
The ‘230 application is drawn to a pharmaceutical composition, wherein the pharmaceutical composition comprises an IL-15 variant fusion protein, a buffer, a protein stabilizer, and a surfactant, wherein the IL-15 variant fusion protein comprises the following domains: (1) an IL-15 variant; (2) an immunoglobulin molecule fused to the IL-15 variant; and (3) IL-15Ra; wherein the amino acid sequence of the IL-15 variant is set forth in SEQ ID NO: 5, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 7; wherein the amino acid sequence of wild-type IL-15 is set forth in SEQ ID NO: 1; wherein the order in which the domains in the IL-15 variant fusion protein are linked from the N-terminus to the C-terminus is: an immunoglobulin molecule, IL-15Ra, and an IL-15 variant; wherein the IL-15Ra or the IL-15 variant is fused to the C-terminus of the immunoglobulin Fc region; and wherein the immunoglobulin molecule is an anti-PD-L1 antibody, the heavy chain of the anti-PD-L1 antibody has the sequence set forth in SEQ ID NO: 19 or SEQ ID NO: 20, and the light chain of the anti-PD-L1 antibody has the sequence set forth in SEQ ID NO: 21 (see claim 1). SEQ ID NOs: 5, 19, and 21 of the ‘230 application share 100% identity with instant SEQ ID NO: 45, 61, and 63, respectively.
The ’230 application is drawn to the pharmaceutical composition according to claim 1, wherein the IL-15 variant is fused to IL-15Ra with a linker peptide, and is then fused to the immunoglobulin molecule (see claim 8). The ‘230 application is drawn to the pharmaceutical composition according to claim 8, wherein the linker peptide has the sequence set forth in SEQ ID NO: 13, SEQ ID NO: 15, or SEQ ID NO: 16 (see claim 9). SEQ ID Nos: 13 and 16 of the ‘230 application share 100% identity with instant SEQ ID Nos: 65 and 71, respectively.
The difference between the instant claims and the ‘230 application is that the ‘230 application is also drawn to methods of using the claimed pharmaceutical compositions. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121.
As such, the ‘230 application anticipates the present invention. This is a provisional nonstatutory double patenting rejection.
Applicant’s Arguments
Applicant respectfully requests that the provisional double patenting rejection be held in abeyance until the present claims are deemed allowable (see page 11 of the Remarks filed 03/02/2026).
Response to Arguments
Applicant's arguments filed 03/02/2026 have been fully considered but they are not persuasive. Applicant is reminded that a request for a rejection to be held in abeyance does not “distinctly and specifically points out the supposed errors in the examiner’s action” as required under 37 CFR 1.111. See MPEP 714.02.
Further, Applicant is advised that a rejection under double patenting precludes the identification of allowable subject matter. Applicant has not filed a terminal disclaimer, and the claims remain rejected for reasons set forth above.
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As such, the double patenting rejection is maintained.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Eisenman et al (CYTOKINE, Vol. 20, No. 3 (7 November), 2002: pp 121–129) disclose of IL-15 interactions with IL-15 receptor complexes (see entire document). Specifically, Eisenman et al disclose of an IL-15 mutant comprising D8S mutation does not alter IL-15Rα binding domain and this mutant form of IL-15 is capable of competitive inhibition of the in vitro activity of IL-15 (see page 122, left col.).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached at (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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