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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/13/2025 has been entered.
Election/Restrictions
Applicant's election with traverse of the species: poly(alkylene oxide), from about 100 to about 200 amino acids residues, linker at K248 amino acid residue, an immune cell target molecule, cytokine, and a modified interleukin 2 (IL-2) in the reply filed on 08/28/2024 is acknowledged. The traversal is on the ground(s) that the application contains “novel and nonobvious class of protein/antibody conjugates” and thus, nothing in the prior art teaches or suggests that the species would be a burden to separate in order to examine. This is not found persuasive because the extent of the prior art is not fully realized at the time of restriction. If the claimed subject matter is deemed novel and qualifies for a rejoinder of claims, the restriction requirement will be withdrawn and all species examined. The requirement is still deemed proper and is therefore made FINAL.
Claim 35 is withdrawn from consideration pursuant to 37 CFR1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 08/28/2024.
Claims 1, 9, 11, 13-14, 17, 30-31, and 38 are now under consideration in the instant Office Action.
Withdrawn Rejections
Rejections of claims 1, 5, 9, 11-14, 17, 21-22, 30-31, and 37-38 under 35 U.S.C. 103 as being unpatentable over Ptacin et al. (US 20190314455, in PTO-892 filed 09/28/2024), in view of Ito et al. (US 20180141976, in PTO-892 filed 09/28/2024) are hereby withdrawn in view of amendments to the claims and Applicant’s arguments over the prior art.
Modified Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 9, 11, 13-14, 17, 30-31, and 38 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 claims are drawn to a composition comprising: an antibody or antigen binding fragment; a recombinant or synthetic protein, wherein the protein is a modified IL2 polypeptide; and a chemical linker, wherein the linker comprises a chemical polymer.
Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 19 USPQ2d 1111, (Fed. Cir. 1991), states 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, for purposes of the written description inquiry, is whatever is now claimed (see page 1117).
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(1), the court states, “An adequate written description of a DNA ... 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.”
The claims recite generic and incompletely described composition components comprising an antibody or antigen binding fragment, a modified IL-2 polypeptide, and a chemical polymer linker. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed composition without adequate descriptions of its component parts or overall makeup. The generically claimed antibody or antigen binding fragment, a modified IL-2 polypeptide, and a linker 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 compositions as recited in the claims, as written. For instance, without knowing the structure of the claimed antibody which selectively binds to a target, one would not be able to adequately describe the claimed composition. Although the specification provides a laundry list of anti-PD-1 antibodies, the instant claims are not limited to all anti-PD-1 antibodies listed and broadly encompass any antibody that selectively binds to a cancer antigen, an immune cell target molecule, or a self-antigen. Similarly, the claims teach that the composition comprises a modified IL2 having at least 80% sequence identity to the SEQ ID NO: 3 while leaving up to 20% of the protein without description of specific modifications. Although the specification teaches that the modification can encompass mutations, addition of various functionalities, deletion of amino acids, or any other alteration of the wild-type version of the protein or protein fragment, this is not a complete description of the IL2 cytokine itself. Given the numerous options provided for the “modification”, there are hundreds, if not thousands of IL2 polypeptides encompassed by the claims. Lastly, the claims state that the composition comprises a linker between the modified IL2 polypeptide and a second point of attachment to the antibody or antigen binding fragment. While some dependent claims recite the point of attachment, this is not a recitation of the linker itself. Thus, the claims identify the composition components solely by their function and/or partial structure. However, with the exception of the fully described compositions disclosed in the specification, the specification provides no guidance regarding the compositions having the claimed function(s). Therefore, the specification fails to provide adequate written description to support the genus of fusion polypeptides encompassed by the claims.
The specification does not provide adequate written description to identify the broad genus of the claims because, inter alia, the specification does not disclose a correlation between the necessary structure of the composition and the claimed function(s) to be maintained; and thus, the specification does not distinguish the claimed genus from others, except by function. Accordingly, the specification does not define the structural features commonly possessed by the genus, because, while the description of an ability of the claimed protein may generically describe the protein’s function, it does not describe the protein itself. A definition by function does not suffice to define the genus because it is only an indication of what the protein 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 compositions is highly variable (i.e., each composition would necessarily have a unique structure, See MPEP 2434), the generic description of the composition is insufficient to describe the genus. Further, given the highly diverse nature of proteins, even one of skill in the art cannot envision the structure of the compositions by knowing a partial structure and its functional characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of compositions claimed only by a functional characteristic 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 compositions has no correlation between their structure and function.
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between the fully disclosed compositions (e.g., antibody conjugates comprising pembrolizumab or LZM-009 conjugated to IL-2 polypeptide AB or AC (see paragraph 0101 and Example 1), and the claimed function(s), this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed antibody conjugates, and broadly encompass conjugates comprising any antibody or antigen binding fragment joined to a modified IL2, comprising any number of modifications, and linked via any chemical polymer. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a few species have been described and this is not considered to be representative of the breadth of the genus.
MPEP §2163 states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance (as in the instant case), the disclosure must describe a sufficient variety of species to reflect the variation within that genus. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number to adequately describe a broad genus. The courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus (e.g., see In re Gostelli, 872, F. 2d at 1012, 10 USPQ2d at 1618).
Further, the disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the genu[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when… the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Accordingly, the specification also does not provide adequate written description to identify the broad genus of the claimed, claimed only by a partial structure and a functional 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 compositions 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).
Vas-Cath Inc. v. Mahurkar, 19 U5PQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
With the exception of the fully described antibody conjugates set forth in the specification, the skilled artisan cannot envision the detailed chemical structure of the encompassed compositions 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 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.
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.
In Ariad Pharms., Inc. v. Eh Lilly & Co., 598 F.3d 1336,1351 (Fed. Cir. 2010), the court held that a “sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize’ the members of the genus." Ariad, 598 F.Bd at 1350.
“[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials,” Id. Although “functional claim language can meet the written description requirement when the art has established a correlation between structure and function," "merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.” Id.
The state of the art regarding the unpredictability of antibody-active agents for treating diseases is discussed by Casi et al. (in PTO-892 filed 09/28/2024). Casi et al. state that “Although the concept of antibody–drug conjugates (ADCs) appear simple, the development of efficacious products often represents a considerable challenge” (See page 422). Casi et al. teach that many parameters have to be optimized for a successful ADC product, some of which are specific to individual tumor types (See page 422). Casi et al. teach the first-generation ADC BR96-doxorubicin, comprising BR-96 chimeric antibody conjugated to doxorubicin, is a prominent example of the uncertainty in ADC development. Casi et al. teach that a phase I clinical trial confirmed the ability of the immunoconjugate to deliver doxorubicin to the tumor cells; however, despite that higher total serum levels of doxorubicin were achieved compared to iv administration, dose-limiting toxicities were not the same as conventional doxorubicin-related adverse events (See page 423). Casi et al. teach that a subsequent randomized phase II trial on a population with confirmed sensitivity to doxorubicin revealed that the toxicities might have been of gastrointestinal origin, due to normal gut expression of LewisY (See page 423). Casi et al. teach that in both trials, little antitumor activity was observed. Therefore, the normal tissue cross-reactivity of BR96 and the low molar potency of doxorubicin represented clear limitations for the industrial development of BR96-doxorubicin (See page 423). Casi et al. also teach that when developing ADCs, consideration must be given to antibodies and the antibody format, drug choice and cleavable linker (See page 423). Given the teachings of Casi et al., one of skill in the art would need guidance when developing an ADC for treating a disease. Casi et al. make it clear that designing ADCs is not merely combining antibodies and drugs known in the art for treating cancer. It is not readily predictable that a particular conjugate would show efficacy, based on the individual components of the conjugate showing efficacy. As taught by Casi et al., ADC BR96-doxorubicin showed little antitumor activity, even though doxorubicin is known to show antitumor activity as monotherapy.
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. (in PTO-892 filed 09/28/2024) 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. (in PTO-892 filed 09/28/2024) 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. (in PTO-892 filed 09/28/2024) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Whisstock et al. (in PTO-892 filed 09/28/2024) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue falls. Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323). Given not only the teachings of Bowie et al., Lazar et al. and Burgess et al. but also the limitations and pitfalls of assigning a function to an amino acid sequence based upon similarity as taught by Whisstock, the claimed proteins could not be predicted. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the agent per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
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 fusion proteins. 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 fusion 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 conjugate such that one would be able to distinguish it from the conjugates 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 compositions 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.” Lizardtech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724, 1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the genus. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
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).
Response to Arguments
Applicant's arguments filed 10/13/2025 have been fully considered but they are not persuasive.
Applicant argues the claims have been amended to recite that the antibody is an IgG1 or IgG4 antibody and that the cytokine is selected from modified IL-2, modified IL-7, and modified IL-18 having at least 80% sequence identity to wild type human sequences of those cytokines. This is not found persuasive.
While the amendments to the claims provide additional structural information regarding the cytokines that are conjugated to the antibody, there are still significant structural details that remain missing in order to satisfy the written description requirement. The instant claims still read on a large, undefined category of antibodies which Applicant has not fully shown possession of, as well as undefined variability in the modified IL-2 cytokine sequence. Applicant has provided some examples in the instant specification of conjugates of a variety of cytokines (see, e.g., Table 10 of the instant application), including IL-2 polypeptides (e.g., CMP-003 CMP-010, and CMP- 086 as described in the application) and IL-7 polypeptides (e.g., CMP-095) conjugated to a wide variety of antibodies (e.g., antibodies targeting PD-1 (Pembrolizumab, J43, LZM-009), PD-L1 (Durvalumab), CD20 (Rituximab), TNFa (Adalimumab, Infliximab), and HER2 (Trastuzumab)) at the points of attachment recited in the claims.
However, it is noted that the features upon which applicant relies (i.e., the structure and/or identity for the antibody of the claimed invention, structure of the conjugated cytokine, and the structure of the linker) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). As currently recited, the instant claims do not recite the level of detail that is disclosed in the instant specification. Instead, the instant claims as written encompass any conjugate comprising any IgG1 or IgG4 antibody which selectively binds to a cancer antigen, an immune cell target molecule, a self-antigen, a modified cytokine selected from IL-2, IL-7, and IL-18, connected by any chemical polymer linker. As such, Applicant has not shown possession of all conjugates or molecules that fall under the extremely broad claim language, which encompasses a large, unknown amount of potential conjugates defined only by their function and without structure or identity. Applicant is invited to amend the claims to draw upon embodiments listed in the specification to include greater detail regarding limitations of the claimed invention.
Therefore, the rejection is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1, 9, 11, 13-14, 17, 30-31, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Hutmacher et al. 2019 (in instant PTO-892), in view of Ptacin et al. (US 20190314455, in PTO-892 filed 09/28/2024), and Ito et al. (US 20180141976, in PTO-892 filed 09/28/2024).
Hutmacher et al. investigates the therapeutic potential of immune checkpoint inhibitors in combination with F8-IL2, a tumor-targeting antibody-IL2 fusion protein. Hutmacher et al. find that “an antibody-IL2 fusion protein capable of selective localization to the tumor site, in combination with antibodies against murine CTLA-4, PD-1, and PD-L1. In immunocompetent mice bearing CT26 tumors, the combination of F8-IL2 with CTLA-4 blockade was efficacious, leading to increased progression-free survival and protective immunity against subsequent tumor re-challenges”, see Abstract. Hutmacher et al. teaches that “various strategies have been considered in order to increase the therapeutic index of IL2. For example, Nektar Therapeutics has developed NKTR-214, an IL2 derivative featuring an average of six releasable polyethylene glycol (PEG) chains (4). NKTR-214 has shown promising activity when used in combination with antibodies specific to CTLA-4 or PD-1 (4). An alternative strategy for the enhancement of IL2 activity and specificity relies on the antibody-based delivery of this immunostimulatory payload to the tumor environment”, see Introduction. Hutmacher et al. concludes that “the results of our study support the use of targeted IL2 in combination with checkpoint inhibitors for cancer therapy”, see Introduction.
Hutmacher et al. reviews the results of the experimentation and notes that “F8-IL2 displayed a potent tumor growth inhibition compared to the saline control, but complete remission was observed only in a small proportion of treated mice. Similarly, antibodies directed against CTLA-4, PD-1, and PD-L1 had single-agent activity, but also only rarely led to complete tumor control [Fig. 2]. The combination of F8-IL2 with CTLA-4 blockade led to complete and durable responses in all treated animals”, see Therapy Experiments. The teachings of Hutmacher et al. meets the limitations of instant claims 1, 9, and 11 wherein the conjugate comprises an antibody (from the list of anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies), a cytokine comprising a modified interleukin 2 (IL2 polypeptides), and linkers comprising a chemical polymer (e.g. polyethylene glycol, a species of poly(alkylene oxides)).
However, Hutmacher et al. is silent regarding the point of attachment of the linker on the antibody within the conjugate. Ptacin et al. remedies this deficiency.
Ptacin et al. teach that an IL-2 polypeptide which comprises a water-soluble polymer (e.g., polyethylene glycol or a poly(alkylene oxide)), and the IL-2 conjugate is indirectly bound to the antibody with a linker (See paragraphs 0136-0138, 0179, and 0382). Ptacin et al. also teach that the IL-2 polypeptide is conjugated to an Fc portion of an antibody and the polypeptide is conjugated to an Fc portion of an Fc portion of IgG (e.g., IgG1, IgG3, or IgG4) (see paragraph 0176). Ptacin et al. teaches that the antibody which is comprised in a conjugate can be a monoclonal antibody and can be an IgG4 antibody (see paragraph 0233).
However, Hutmacher et al. and Ptacin et al. are silent on site-specific attachment at an Fc region of the antibody at the amino acid residue K248 according to EU numbering. Ito et al. remedies this deficiency.
Ito teaches a method of site-specific conjugating any protein of interest to the Fc region of IgG, e.g., Lys 248, Lys 246, according to the EU numbering of human IgG Fc using IgG-binding peptide as linker, see entire document, para. [0253], [0259]. After substitution of the 6th amino acid of DCAYHRGELVWCT (SEQ ID NO: 33) by Lys, a cross-linked structure via DSG or DSS was converted to a model in a form having a linkage between the ε amino group of this Lys and the ε amino group of Lys at position 248 of the antibody Fc, see para. [0287]. Ito teaches the Fc affinity peptide can be modified with an amino-PEG4 [polyethylene glycols] added synthetic peptide with C-terminally amidated) with the amino group modified with biotin, see Example 2, para. [0289] or DSG-modified N-terminally azidated IgG-binding peptide (SEQ ID NO: 2) wherein X represents DSG-modified lysine, the two Cys residues formed an intramolecular SS bond, and the C-terminus was amidated (see Example 9, para. [0310]. The modified IgG-binding peptide and the IgG antibody to which the modified IgG-binding peptide is bound make it possible to link a ligand to the modified IgG-binding peptide or the IgG antibody by a ligand having an azido group that can bind to DBCO in a click reaction, see para. [0311].
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art to use the teachings of Hutmacher et al., which display success when using a cancer antigen selective antibody in a modified IL2 conjugate linked by a polyethylene glycol linker, with the teachings of Ito which discloses Fc affinity peptide mediated region divergent functionalization of native mAb antibody to site-specific alterations at position K248 of the Fc region of an antibody capable of conjugation, with the teachings of Ptacin et al. who disclose possible modifications to IL-2 polypeptides. One of ordinary skill in the art would have been motivated to do so because Ito teaches that the method does not involve the engineering of antibodies themselves, see para. [0253], Hutmacher et al. teaches that the antibody-IL2 fusion conjugate is capable of selectively localizing to tumor sites and effectively killing cancer cells, and Ptacin et al. teaches modifications to antibody conjugates comprising IL-2 modified polypeptides. The combination of references instructs one of ordinary skill in the art to effective methods of targeting tumors through selecting antibodies selective to cancer antigen (Hutmacher et al.), potential modifications that are beneficial to the therapeutic effects of modified IL2 conjugates (Ptacin et al.), and the rationale between selecting a site for a linkers on an antibody without interfering with the therapeutic function of the larger construct (Ito et al.) Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Therefore, claims 1, 9, 11, 13-14, 17, 30-31, and 38 are rejected as obvious over Hutmacher et al., Ptacin et al., and Ito et al.
Response to Arguments
Applicant's arguments filed 10/13/2025 have been fully considered and are considered persuasive.
Applicant argues that Ptacin et al. teaches the potential administration of an immune checkpoint inhibitor antibodies as a separate, additional therapeutic agent and not one comprised within the antibody-conjugate. This is found persuasive.
As such, the modified rejection no longer relies upon Ptacin et al. to teach those specification limitations. A new reference, Hutmacher et al., is now incorporated in the rejection to address the modified claim limitations. Ptacin et al. continues to be invoked in the rejection; however, it is used to teach other dependent claim limitations and not those which Applicant has identified as not anticipating the claim limitations.
Therefore, the rejection has been modified in view of amendments to the claims and Applicant’s arguments.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SELAM BERHANE whose telephone number is (571)272-6138. The examiner can normally be reached Monday - Friday, 9-5.
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675