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
The Amendment filed 5/4/2026 in response to Office Action of 11/3/2025, is acknowledged and has been entered. Claims 80-86 and 94-103 are now pending. Claims 80 and 97 are amended. Claims 99-103 are new.
The Double patent rejections are hereby withdrawn in view of Terminal Disclaimers that were approved on 5/4/2026.
Claims 80-86 and 94-103 are currently being examined.
Claim Objections
Claim 100 is objected to because of the following informalities: the term "activating" is misspelled . Appropriate correction is required.
Maintained Rejection
(Arguments addressed)
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 80-86 and 94-103 remain 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. This is a written description rejection.
The claims are drawn to a conditionally active IL-2 comprising a fusion polypeptide that is covalently or noncovalently bounded to a second polypeptide, wherein the fusion polypeptide comprises a IL-2 polypeptide [A], a IL-2 blocking moiety [D], a half-life extension moiety [H], and a protease-cleavable polypeptide linker; wherein the second polypeptide and the IL-2 blocking moiety of the fusion polypeptide are complementary and together form a functional binding site for the IL-2 polypeptide that is a Fab fragment of an antibody; wherein the IL-2 blocking moiety is VH-CH1 and the second polypeptide comprises a complementary VL-CL, or the blocking moiety is VL-CL and the second polypeptide comprises a complementary VH-CH1. The claims recite that the function is to bind to IL-2 receptor, and treat cane. No structure of the fusion protein containing the IL-2 polypeptide, the IL-2 blocking moiety, or the second polypeptide is recited.
The instant specification discloses the following:
Fusion protein containing the IL-2 polypeptide: The instant specification states that fusion protein containing the IL-2 polypeptide can comprise or consist of the amino acid sequence of any one of SEQ ID NOs. 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608 and 636-646. The fusion proteins disclosed as SEQ ID NOs. 257-300, 302-317, 325-353, 355-365, 366, 372-381, 383-385, 388-420, 579-608, and 636-646 are also referred to herein as ACP289-ACP292, ACP296-ACP302, WW0301, ACP304-ACP306, ACP309-ACP313, WW0353, ACP414, ACP336-ACP398, WW0472-WW0477, ACP406-ACP426, ACP439-ACP447, ACP451-ACP471, WW0729, WW0734-WW0792, ACP101, ACP293-ACP295, ACP316-ACP335, ACP427-ACP438, and ACP448-ACP450. [0194]
IL-2 blocking moiety: The instant specification defines a “blocking moiety” as any moiety that inhibits the ability of the cytokine to bind and/or activate its receptor, and lists examples that include “the full length or a cytokine-binding fragment or mutein of the cognate receptor of the cytokine. Antibodies and fragments thereof including, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody a single chain variable fragment (scFv), single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain of camelid-type nanobody (VHH), a dAb and the like that bind the cytokine can also be used.” [0152]
Second polypeptide: The instant specification discloses that the second polypeptide can contain an antibody light chain VL-CL that comprises or consists of the amino acid sequence of SEQ ID NO: 263, 264, or 333. Such a second polypeptide can bond with a complimentary VH-CH1 polypeptide contained within the fusion protein, e.g., as contained within SEQ ID NOS: 362, 363, 325, 286, 579, 581, or 582. The second polypeptide chain disclosed as SEQ ID NOs. 263, 264, and 333 can be referred herein as WW0523 (ACP381), WW0524 (ACP382), or WW0556 (ACP414). [0013]
It is well established in the art that predicting any protein function from any sequence and structure is a difficult problem. Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2003) teaches that although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge [pg 309] Whisstock teaches 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 teaches 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 [pg 321-323] Bowie et al (Deciphering the message in protein sequences: tolerance to amino acid substitutions. Science. 1990 Mar 16;247(4948):1306-10) teaches 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 3-D structures that allows them to function and carry out the instructions of the genome. Bowie et al 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 [pg 1306] Bowie et al. further teaches 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 3-D structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all [page 1306] Burgess et al. (Possible dissociation of the heparin-binding and mitogenic activities of heparin-binding (acidic fibroblast) growth factor-1 from its receptor-binding activities by site-directed mutagenesis of a single lysine residue. J Cell Biol. 1990;111(5 Pt 1):2129-2138) and Lazar et al (Transforming growth factor alpha: mutation of aspartic acid 47 and leucine 48 results in different biological activities. Mol Cell Biol. 1988 Mar;8(3):1247-52) both teach that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
With regards to the IL-2 binding moiety, the second polypeptide drawn to antibody fragments, antibodies, etc, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
With regards to IL-2 blocking moieties, Tang et al. (The challenges and molecular approaches surrounding interleukin-2-based therapeutics in cancer. Cytokine X. 2018;1(1):100001. Published 2018 Dec 10) teaches the challenges of approaches surrounding IL-2 based therapeutics. [pg 2] Tang et al teaches that IL-2 based therapies bear the risk of immunogenicity and the formation of anti-drug antibodies, and that many factors contribute to the development of these responses including changes in amino acid sequence. [pg 4, 3.1.4 Potential immunogenicity of IL-2 biologics] Thus, the Applicant has not provided any descriptive support for any IL-2 blocking moiety, comprising any structure, to function to inhibit IL-2.
To provide adequate written description and evidence of possession of the claimed composition fusion protein and second polypeptide, the instant specification can structurally describe representative polypeptides, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
Although Applicants may argue that it is possible to screen for proteins that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n 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.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The IL-2 antigen provides no information about the structure of any protein or polypeptide that inhibits it.
Given the lack of representative examples to support the full scope of the claimed products, as demonstrated in the specification and prior art, and lack of reasonable structure-function correlation with regards to the unknown sequences, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of any of the components that function as claimed.
Response to Arguments
Applicant argues that the specification contains adequate written description of the claimed invention. Applicant argues the following:
The claimed invention is defined by structural and functional features: Applicant argues that there are numerous working examples representative of the conditionally active IL-2 comprising a fusion polypeptide that is covalently or noncovalently bonded to a second polypeptide as claimed. Applicant argues that each component is well known by persons of skill in the art.
IL-2 cytokine polypeptide component: Applicant argues that IL-2 is a canonical and well-characterized interleukin in the art.
IL-2 blocking moiety: Applicant argues that that antibodies and/or antigen-binding fragments are well known and extensively described in the prior art and commonly used.
Half-life extension moieties: Applicant argues that that the use of human serum albumin or antigen-binding fragments that bind to human serum albumin is well-established in the art
Protease cleavable linkers: Applicant argues that these are well known in the art and the specification provides clear description and guidance on both structural and functional features of the protease cleavable linkers
Overall makeup: Applicant argues that the application contains extensive description of the overall makeup of the claimed conditionally active IL-2 and points to Table 3, Figure 1, 2, 3,a and 9. Applicant also points to in vivo anti-tumor efficacy in the specification and the amino acid sequences of the representative species.
The specification discloses a large number of representative conditionally active IL-2s encompassed by the claimed invention: Applicant points to Table A (which lists 18 examples) and Table 3 which Applicant states describes each of the construct’s particular elements and the configuration of such elements
Applicant’s arguments have been considered but are not persuasive. The written description is drawn to specific components of the conditionally active IL-2: the fusion polypeptide comprising an IL-2 polypeptide, the IL-2 blocking moiety, and the second polypeptide. Examiner did not reference the half-life extension or protease cleavable linkers in the argument. No structure of these components with the fusion protein is provided within the claims, and the specification lacks written description for these components. As noted in the written description above, predicting protein function from any sequence and structure is a difficult problem. While the Examiner agrees that IL-2 cytokines are known in the art and antibodies and/or antigen-binding fragments are extensively described in the prior art and commonly used, proteins that bind to IL-2 or inhibit it are not well known in the art. It was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody. Furthermore, the art also teaches the challenges surrounding IL-2 based therapeutics. [see Tang above]. The examples of the complete fusion protein in the specification and does not provide enough guidance in the art or possession of the claimed conditionally active-IL2. Table 1A provides 18 examples, and Table 3 is not limited to IL-2 examples and each structure contains a different second polypeptide. The structure of the antibodies is necessary in order to determine the function as recited in the 112(a) rejection above.
Maintained Rejection
(Arguments and Amendments Addressed)
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) 80-84, 86, and 94-103 remain rejected under 35 U.S.C. 103 as being unpatentable over Frellinger et al (US20130089516 A1; Published 4/11/2013), in view of Du et al (US20190241886 A1; Filed 2/1/2019) and Sleep et al (Albumin as a versatile platform for drug half-life extension. Biochim Biophys Acta. 2013 Dec;1830(12):5526-34; of record).
Frellinger et al teaches chimeric polypeptides, comprising (1) a first polypeptide comprising an IL-2 polypeptide “[A]”. (2) a second polypeptide comprising an amino acid sequence that is capable of being cleaved by a protease, and (3) a third polypeptide that blocks the activity of IL-2 “[D]”. [0023, 0028] Frellinger teaches that the protease cleavable polypeptide is provided to be cleaved by a protease that is specifically expressed at the intended target of the active agent. Frellinger teaches that cleavage of the second polypeptide by the protease results in an increase of activity of the first polypeptide (the IL-2 polypeptide) at the site, and increase of biologically active IL-2. [0095] Regarding claim 94, teaches the use of these chimeric polypeptides to treat cancer. [0039] Regarding claims 95-98, teaches methods of making the pharmaceutical comprising, comprising the host cell comprising a vector comprising the nucleic acid encoding the fusion conditionally active IL-2.[0050-0052] Regarding claim 100, Frellinger teaches that the IL-2 receptor activating activity was assessed using a CTLL-2 proliferation assay. [0016] Regarding claims 101 and 103, Frellinger teaches that the protease-cleavable linker comprises a sequence that is capable of being cleaved by a protease, such as cathepsin or matrix metalloproteinase (MMP), such as MMP2. [0026]
However, Frellinger does not teach: (1) that the chimeric polypeptide comprises a second polypeptide that is complementary with the IL-2 blocking moiety to form a Fab fragment to bind to the IL-2 polypeptide, (2) does not teach the half-life extension moiety that is human serum albumin, and (3) the limitations of claim 103.
Du et al teaches methods of making and using activatable antibodies. Du teaches that these activatable binding polypeptides exhibit an “activatable” confirmation, such that an antigen binding moiety contained therein is less accessible to bind to its target when uncleaved than after cleavage in the presence of one or more specific proteases. [0004, 0014] Du teaches that these polypeptides comprise: a first polypeptide, a cleavable moiety, and a target binding moiety. Du teaches that the target binding moiety comprises an antibody light chain variable and/or an antibody heavy chain variable region, and that a Fab fragment is formed. Du teaches that the target binding moiety comprises an amino acid sequence that binds to a target. [0007, 0012, 0067, 0096-0098] Du teaches that the protease-cleavable linker comprises a sequence that is capable of being cleaved by a protease, such as cathepsin, such as cathepsin D or E, B, C, or K, or matrix metalloproteinase (MMP), such as MMP2. [0009, 0153-0154]
Sleep et al teaches the use of albumin for drug half-life extension. Sleep teaches human albumin extends the half-life of therapeutics due to being above the renal threshold, specific interaction and recycling FcRn and a long circulatory half-life of 19 days and can be used in fusion therapeutic molecules. [abstract, whole document]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to construct the polypeptide of Frellinger to include (1) a second polypeptide that is complementary to the IL-2 blocking peptide to form a Fab, and (2) a half-life extension moiety, as well as a protease cleavable linker. One would have been motivated to, and have a reasonable expectation of success, because: (1) Frellinger et al teaches chimeric polypeptides, comprising (1) a first polypeptide comprising an IL-2 polypeptide “[A]”. (2) a second polypeptide comprising an amino acid sequence that is capable of being cleave by a protease, and (3) a third polypeptide that blocks the activity of IL-2 “[D]”, (2) Frellinger teaches that that the protease linkers may be cathepsin or MMP, (3) Du et al teaches known methods of making activable polypeptides with cleavage linkers, a target, and a blocking moiety, wherein the blocking moiety comprises a Fab fragment with another polypeptide, (4) Du teaches that the cleavage linkers includes protease linkers, such as cathepsins and MMP, and (5) Sleep et al teaches known methods of using serum albumin to extend the half-life of therapeutics, including fusion proteins.
Response to Arguments
Applicant argues that there is no motivation to modify the IL-2 fusion protein of Frelinger to arrive at the claimed conditionally active IL-2s. Applicant argues that Frelinger discloses that an active protease expressed by tumor cells leaves IL-2 fusion protein which leads to the dissociation of IL-2 from the binding moiety and release of active IL-2. Applicant argues that Frelinger does not mention or suggest an IL-2 fusion protein having a half-life extension. Applicant argues that Sleep provides a general review of using albumin for extending circulating the half-life of therapeutic agents and does not suggest that it can be suitable for the claimed conditionally active IL-2. Applicant argues that it adding a half-life extension of IL-2 was not considered a viable approach to reduce side effects or to preferentially stimulate particular immune cells.
Applicant argues that the addition of a half-life extension element to the protease-activated IL-2 fusion proteins disclosed by Frelinger would be counter-intuitive and contrary to the clear direction away from this approach in the prior art. Applicant argues that it is clear that extending the half-life of IL-2 would increase systemic exposure to active IL-2, and this would also be expected for IL-2 with attenuated activity. Applicant argues that given the well-known toxicities of highly potent IL-2 it would be undesirable, and perhaps reckless, to clinically use longer acting versions of these proteins to promote anti-tumor responses. Applicant argues that even if a POSA were to add this link, they would not have a reasonable expectation of success that the fusion protein would be therapeutically effective and reduce systemic toxicity. Applicant argues that Du fails to cure the deficiencies in Frelinger alone or in combination with Sleep.
Applicant’s arguments have been considered but are not persuasive. To reiterate the teachings of the prior art, Frellinger et al teaches chimeric polypeptides, comprising (1) a first polypeptide comprising an IL-2 polypeptide “[A]”. (2) a second polypeptide comprising an amino acid sequence that is capable of being cleaved by a protease, and (3) a third polypeptide that blocks the activity of IL-2 “[D]”. Thus, Frelinger teaches the structure of the claimed product. Examiner acknowledges that Frelinger does not teach the half-life extension and relied on the combination of references to render this obvious. The purpose of the secondary references is to remedy the deficiency of Frelinger. The purpose of Du is to demonstrate known methods of making “activable polypeptides”, and the purpose of Sleep is to demonstrate known methods of using serum albumin to extend half-life of therapeutics, including fusion proteins. Thus, given the known methods and mechanism of adding a half-life extension, and given the known methods of making activable proteins, as taught by the prior art, one of skilled in the art could have pursued adding a half-life extension to Frelinger, with a reasonable expectation of success
Conclusion
THIS ACTION IS MADE FINAL. 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 SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
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/SARAH A ALSOMAIRY/ Examiner, Art Unit 1646
/Zachariah Lucas/ Supervisory Patent Examiner, Art Unit 1600
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