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
In view of new claims (claims 80-98), the restriction sent out 6/18/2025 is no longer applicable. Claims 80-98 are currently under prosecution.
Information Disclosure Statement
The information disclosure statements filed 10/27/2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: claim 80 recites ". The claim should recite “an” rather than “a”. Appropriate correction is required.
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 80-98 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. 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.
Dependent claim 88 recite: (i) the fusion polypeptide comprises an amino acid sequence that has at least 80% identity to the SEQ ID Nos: 286, 325, 362, 363, 579, 581 or 582; and (ii) the second polypeptide sequence comprises an amino acid sequence that has at least 80% identity to SEQ ID NO: 263, 264, or 333. Thus, the claim defines the fusion protein and second polypeptide sequence by partial sequence, allowing for up 20% sequence discrepancy.
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]
Partial structure: The instant specification fails to disclose any representative variants comprising less than 100% of the SEQ ID Nos: of the fusion polypeptide or the second polypeptide.
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.
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 94-98 are 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).
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]
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 and (2) does not teach the half-life extension moiety that is human serum albumin
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]
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. 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) 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, and (3) Sleep et al teaches known methods of using serum albumin to extend the half-life of therapeutics, including fusion proteins.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 80-84, 86, and 95-98 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10,696,724. Although the claims at issue are not identical, they are not patentably distinct from each other because the U.S. Patent recites a fusion polypeptide of the formula: [A]-[L1]-[D]-[L2’]-[B], wherein [A] is the IL-2 polypeptide, [L1] is the protease-cleavable polypeptide linker, [D] is the IL-2 blocking moiety, [L2’] is a protease-cleavable polypeptide linker, and [B] is the half-life extension moiety, human serum albumin or antigen binding fragment that binds to human serum albumin. The U.S. patent recites that the fusion polypeptide has attenuated IL-2 receptor activating activity, wherein the IL-2 receptor has 10-fold less than the IL-2 receptor activating activity of the polypeptide that comprises the IL-2 polypeptide that is produced by cleavage of the protease-cleavable polypeptide linker. The U.S. Patent recites that the antibody fragment that binds to IL-2 polypeptide is a Fab.
Claims 80-84, 86 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,352,403 Although the claims at issue are not identical, they are not patentably distinct from each other because the U.S. Patent recites a fusion polypeptide of the formula: [A]-[L1]-[D]-[L2’]-[B], wherein [A] is the IL-2 polypeptide, [L1] is the protease-cleavable polypeptide linker, [D] is the IL-2 blocking moiety, [L2’] is a protease-cleavable polypeptide linker, and [B] is the half-life extension moiety, human serum albumin or antigen binding fragment that binds to human serum albumin. The U.S. patent recites that the fusion polypeptide has attenuated IL-2 receptor activating activity, wherein the IL-2 receptor has 10-fold less than the IL-2 receptor activating activity of the polypeptide that comprises the IL-2 polypeptide that is produced by cleavage of the protease-cleavable polypeptide linker.
Claims 80-84, and 86 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,535,658 Although the claims at issue are not identical, they are not patentably distinct from each other because the U.S. Patent recites a cytokine comprising: (a) first half-life extension domain to a human serum albumin, (b) an IL-2 polypeptide, (c) an IL-2 blocking moiety, wherein the blocking moiety comprises a fragment for IL-2 polypeptide, and is a Fab fragment. The U.S. patent recites that the fusion polypeptide has attenuated IL-2 receptor activating activity, wherein the IL-2 receptor has 10-fold less than the IL-2 receptor activating activity of the polypeptide that comprises the IL-2 polypeptide that is produced by cleavage of the protease-cleavable polypeptide linker. The U.S. Patent recites that the antibody fragment that binds to IL-2 polypeptide is a Fab.
Claims 80-84, and 86 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,275,769. Although the claims at issue are not identical, they are not patentably distinct from each other because the U.S. Patent recites a fusion polypeptide of the formula: [A]-[L1]-[D]-[L2’]-[B], wherein [A] is the IL-2 polypeptide, [L1] is the protease-cleavable polypeptide linker, [D] is the IL-2 blocking moiety, [L2’] is a protease-cleavable polypeptide linker, and [B] is the half-life extension moiety, human serum albumin or antigen binding fragment that binds to human serum albumin. The U.S. patent recites that the fusion polypeptide has attenuated IL-2 receptor activating activity, wherein the IL-2 receptor has 10-fold less than the IL-2 receptor activating activity of the polypeptide that comprises the IL-2 polypeptide that is produced by cleavage of the protease-cleavable polypeptide linker. The U.S. Patent recites that the antibody fragment that binds to IL-2 polypeptide is a Fab.
Claim 80-84, and 86 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 8, and 9 of copending Application No. 18/045,160 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending application recites a conditionally active IL-2 comprising a human IL-2 polypeptide, a half-life extension element, an IL-2 blocking moiety that comprises an antigen-binding fragment that binds to IL-2 polypeptide, such as a Fab, and a protease-cleavable linker.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600