DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/US20/63214 filed on 12/04/2020, which claims the benefit of US Provisional Application No. 62/944,203 filed on 12/05/2019. Claims 2 and 10 do not have support in US Provisional Application No. 62/944,203, because it does not describe wherein the fusion protein comprises a constant region of light chain and a constant region of heavy chain. Therefore, Claims 2 and 10 receive an effective filing date of December 4, 2020 and Claims 1, 3-9, 11-14, and 18-23 receive an effective filing date of December 5, 2019.
Claim Status
Claim listing filed on October 18, 2025 is pending. Claims 15-17 and 24-34 are canceled. Claims 1-14 and 18-23 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements filed on 06/12/2024, 11/22/2024, and 10/29/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: In paragraph [00107] in the 4th line from the bottom, “at least” is repeated twice. Appropriate correction is required.
Claim Objections
Claims 1-3, 7, 9-11, and 14 are objected to because of the following informalities:
Claim 1, line 9 recites “structure unit” and should recite “structural unit” as is presented prior in the claim.
Claim 2, line 12 should recite “and linked with either a short cleavable linker…”
Claim 7, line 3 recites “27aa~137aa” and should recite “27aa-137aa” with a hyphen instead of a tilde.
Claims 9-10 reference Figures 14A and 14B. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience" (see MPEP § 2173.05(s)). Therefore, instead of referencing Figures 14A and 14B, the fusion protein constructs and orientations can be described in words.
Claim 11, line 3 recites “2~4” and should recite “2-4” with a hyphen instead of a tilde.
Appropriate correction is required.
Claim 3 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only. See MPEP § 608.01(n). For the purpose of compact prosecution, Claim 3 is interpreted as “The fusion protein or fusion protein complex of claim 1 or 2…”
Claim 14 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, claim 14 has not been further treated on the merits.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-13 and 18-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-2 recite the limitations "the interleukin 15 (IL15) receptor-α" and "the IL15 receptor β." There is insufficient antecedent basis for these limitations in the claim. There can be different IL-15 receptors (e.g. from different species), and it is unclear what is meant by the IL-15Rα and the IL-15Rβ.
Claim 6 recites 27aa-240aa of IL-15Rβ, and it is unclear what is meant be “27aa-240aa” without a defined reference sequence. Different IL-15Rβ mutational variants or species variants may have different sequence lengths, and it is unclear what is encompassed by “27aa-240aa” in relation to sequences with different lengths. Claims 7-8 are also rejected for indefiniteness for naming amino acid residue positions without a reference sequence. For the purpose of compact prosecution, it is interpreted that the residue positions are in reference to SEQ ID NO: 5 (specification page 50), but appropriate correction is required.
Claims 12-13 recite “a short cleavable flexible linker (L2)” and “a long cleavable flexible linker (L2L)” respectively. It is unclear whether or not these linkers are in reference to the “short cleavable linker (L)” and “long cleavable linker (L2L)” defined in Claims 1-2 or if these linkers indicate new additional linkers. The linkers in Claims 12-13 are called “flexible” wherein the linkers in Claims 1-2 are not. The abbreviations of the short linkers differ (L2 vs L) and the abbreviations of the long linkers are the same (L2L). For the purpose of compact prosecution, it is interpreted that the short cleavable flexible linker and the long cleavable flexible linker of Claims 12-13 are in reference to the linkers defined in Claims 1-2, but appropriate correction is required.
Note, “substantially purified” in Claim 19 is not indefinite, because the term is defined in the specification as a protein isolated and/or purified to obtain a composition containing an amount by weight equal to or greater than 80% (paragraphs [00107]-[00108]). Note, “short cleavable linker” is defined by the specification as linkers having a length in the range of about 10 to about 20 with one cleavable site, and “long cleavable linker” is defined as linkers having a length in the range of about 20 to about 40 with one or two cleavable sites (paragraph [00155]). Note, “connecting segments” and “ligation fragments” in Claims 1-2 are defined by the specification as noncleavable flexible linkers and in some embodiments comprise (GGGS)n (paragraphs [00154] and [00156]).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 11 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 11 recites wherein one of the connecting segments or ligation fragments comprises an amino acid sequence with or without protease sensitive sequences. “Protease sensitive sequences” is interpreted as cleavable sequences; however, Claims 1-2 define wherein the connecting segments or ligations fragments are specifically non-cleavable linkers. Therefore, Claim 11 fails to include the limitations of Claims 1-2 on which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-13 and 18-23 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 claims contain 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.
Claims 1-2 are directed to a fusion protein comprising a whole or a subunit domain of IL-15Rα, IL-15, and a whole or subunit domain of IL-15Rβ. “Subunit domain” is not specifically defined in the specification and is interpreted with the broadest reasonable interpretation to include any fragment of two or more amino acid residues of the whole domain. Further, the specification defines that “IL-15” refers to a polypeptide that has at least 90% sequence identity to a native mammalian IL-15 amino acid sequence and includes mutated IL-15 polypeptides that retain biological function (paragraph [0087]). Similarly, “IL-15Rα” refers to a polypeptide that has at least 90% identity to a native mammalian IL-15Rα amino acid sequence and includes mutated IL-15Rα polypeptides that retain biological function (paragraph [0091]). Therefore, the claims are directed to a genus of fusion proteins that can comprise mutated IL-15, mutated IL-15Rα, any fragment of IL-15Rα, and any fragment of IL-15Rβ.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. In order to provide adequate written description and evidence of possession of this claimed genus of fusion proteins, the specification must provide sufficient distinguishing identifying 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.
In the instant case, the specification teaches two species of fusion protein. The first species comprises mature mouse IL-15, mouse IL-15Rα sushi domain (amino acids 1-78), and mouse IL-15Rβ extracellular domain (amino acids 27-240) (paragraph [00246] and Fig. 2B). The second species comprises the same IL-15 and IL-15Rα domains with mouse IL-15RβD1 (amino acids 27-125) (paragraph [00246] and Fig. 2B). Thus, the specification only provides proper written description for one subunit fragment of IL-15Rα, two subunit fragments of IL-15Rβ, and no guidance on how 10% of the IL-15 and/or IL-15Rα sequences can be mutated without altering biological function.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (MPEP § 2163.05.Ib). In the absence of sufficient recitation of distinguishing identifying characteristics or structure-to-function attributes for the entire genus of fusion proteins, the specification does not provide adequate written description of the claimed genus. Therefore, in view of the case law directed to an appropriate number of representative species, claims 1-13 and 18-23 are rejected for insufficient written description.
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).
Claims 1-13 and 18-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the two species of fusion proteins taught by the specification (paragraph [00246]) and those known in the art prior to filing, does not reasonably provide enablement for the genus of fusion proteins encompassed by the claims. Further, the specification, while being enabling for treating cancer, does not reasonably provide enablement for treating hyperplasia (Claim 23). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
MPEP § 2164.01(a) states that there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure
does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors include, but are not limited to:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention:
The nature of the invention is complex. As understood with the broadest reasonable interpretation, Claims 1-2 are directed to a genus of fusion proteins that can comprise mutated IL-15, mutated IL-15Rα, any fragment of IL-15Rα, and any fragment of IL-15Rβ. Claim 23 recites a method of treating hyperplasia by administering the fusion protein.
When analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be "given their broadest reasonable interpretation consistent with the specification." See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. In AMGEN INC. ET AL. v. SANOFI ET AL. (No. 21-757, decided May 18, 2023), the Supreme Court held that Amgen was not enabled for “the entire genus” of antibodies that (1) “bind to specific amino acid residues on PCSK9,” and (2) “block PCSK9 from binding to [LDL receptors]” (872 F. 3d 1367, 1372) even though Amgen identified the amino acid sequences of 26 antibodies that perform these two functions. The case law applies to the instant claims which encompass a genus of fusion proteins comprising receptors with binding activity, yet the inventors have only disclosed two species of fusion proteins (paragraph [00246]).
In Amgen, the Supreme Court has stated that despite recent advances, aspects of antibody science remain unpredictable. For example, scientists understand that changing even one amino acid in the sequence can alter an antibody's structure and function. See id., at 14. But scientists cannot always accurately predict exactly how trading one amino acid for another will affect an antibody's structure and function. Ibid. The unpredictability of polypeptide structure and function extends to the IL-15, IL-15Rα, and IL-15Rβ domains in the instant application.
The case law shows a continued lack of predictability even after the effective filing date of the instant invention, and there is no support in the Applicant’s disclosure leading one of ordinary skill to overcome the lack of predictability in the genus of fusion proteins claimed. The specification provides no guidance or direction for structure that must be maintained such that the functional properties of the IL-15, IL-15Rα, and IL-15Rβ domains are preserved (receptors binding and/or blocking IL-15).
Lu et al. US 2020/0392235 (effectively filed June 2019) teaches that masked IL-15 cytokines can be administered to treat cancer (paragraphs [0165]-[0167]). However, hyperplasia differs from cancer in that it is an increase in the number of normal cells (not abnormal) in a tissue or organ, causing it to enlarge. There is no evidence in the art that masked IL-15 cytokines can treat hyperplasia, and Mussarat et al. Immunol Cell Biol. 2018 teaches that overexpression of IL-15 in the intestine can promote hyperplasia (title and abstract). The state of the art shows a lack of predictability in treating hyperplasia by administering the IL-15 fusion proteins of the instant claims.
Level of skill in the art:
The level of skill would be high encompassing protein science, binding assays, immunology, in vivo treatment etc.
Amount of direction provided by inventor and the existence of working examples:
The specification teaches two species of fusion protein. The first species comprises mature mouse IL-15, the mouse IL-15Rα sushi domain (amino acids 1-78), and mouse IL-15Rβ extracellular domain (amino acids 27-240) (paragraph [00246] and Fig. 2B). The second species comprises the same IL-15 and IL-15Rα domains with mouse IL-15RβD1 (amino acids 27-125) (paragraph [00246] and Fig. 2B). The specification teaches that the fusion proteins have anti-tumor activity in mouse models of colorectal cancer (MC38 cells) and B-cell lymphoma (A20 cells) (paragraph [00241]).
Thus, the specification only provides enablement for one subunit fragment of IL-15Rα, two subunit fragments of IL-15Rβ, and no guidance on how 10% of the IL-15 and/or IL-15Rα sequences can be mutated without altering biological function. No examples are provided wherein the fusion proteins are administered to treat hyperplasia. Two species do not adequately represent the scope of fusion proteins that can comprise hundreds to thousands of variations in the IL-15, IL-15Rα, and IL-15Rβ domains. A person having ordinary skill in the art would have to make a substantial inventive contribution in order to make and characterize a representative number of fusion proteins and use them to treat cancer and hyperplasia in order to practice the claimed invention.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In light of the unpredictability surrounding the claimed subject matter, the undue breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to make and practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Given that structure is essential to function, a person having ordinary skill in the art would have to perform further experimentation to make the fusion proteins encompassed by the claims and screen their characteristics in order to practice the invention commensurate with the scope of the claims. For in vivo treatment, further experiments would be required, in human clinical trials or in animal models, that are predictive of treatment in a representative number of cancer and hyperplasia types by administering a representative number of fusion proteins in order to demonstrate the invention could be used with a reasonable expectation of success.
The instant specification does not enable the invention to make and use the entire genus of fusion proteins and does not enable the treatment of hyperplasia; therefore, Claims 1-13 and 18-23 are rejected.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3-5, 11-13, and 18-23 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Lu et al. US 2020/0392235 (effectively filed June 2019).
In regard to Claims 1 and 18, Lu teaches a prodrug comprising an IL-15 cytokine, a masking moiety, a carrier moiety, and a sushi domain, wherein the masking moiety binds to the IL-15 cytokine (paragraph [0007]). The carrier moiety can be an Fc domain positioned at the C-terminal of the fusion protein, the masking moiety is linked to the N-terminal of the Fc domain by a cleavable linker, and the IL-15 and IL-15Rα sushi domain are linked with non-cleavable linkers (Fig. 2A). The masking moiety can comprise an extracellular domain of IL-2Rβ (paragraph [0013]). Note, it is understood that IL-2Rβ and IL-15Rβ are the same protein (also called CD122).
In regard to Claim 3, Lu teaches that the IL-15 cytokine is a human IL-15 polypeptide (paragraph [0017]), and the carrier moiety is a human Fc domain (paragraph [0144]).
In regard to Claims 4-5, the IL-15Rα comprises SEQ ID NO: 8 which represents the whole IL-15Rα (paragraph [0072]). Alternatively, the IL-15Rα can comprise the sushi domain subunit (residues 31-95 or 31-105 of SEQ ID NO: 8) (paragraph [0072]).
In regard to Claims 11-13, Lu teaches that the noncleavable linkers can be selected from SEQ ID NOs: 11-16 wherein SEQ ID NO: 11 is 100% identical to instant SEQ ID NO: 18 (paragraph [0024] and page 19). The cleavable linkers can be selected from SEQ ID NOs: 17-36 (paragraph [0025]) wherein SEQ ID NO: 23 comprises 10 amino acid residues and SEQ ID NO: 36 comprises 42 amino acid residues and two cleavable sites (pages 19-20).
In regard to Claim 19, Lu teaches a method of purifying the IL-15 prodrug that results in a substantially purified product (paragraphs [0174] and [0187]-[0189]).
In regard to Claims 20-22, Lu teaches a pharmaceutical composition comprising the IL-15 prodrug and a pharmaceutically acceptable excipient, a polynucleotide encoding the IL-15 prodrug, and an expression vector comprising the polynucleotide (paragraph [0026]).
In regard to Claim 23, Lu teaches a method of treating cancer by administering the IL-15 prodrug to a subject wherein the cancer is a solid cancer or a blood cancer (paragraphs [0165]-[0167]).
Therefore, Claims 1, 3-5, 11-13, and 18-23 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Lu.
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.
Claims 1, 3-9, 11-13, and 18-23 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al. US 2020/0392235 (effectively filed June 2019) in view of Karow et al. WO 2020/069398 (filed September 2019).
The teachings of Lu as they apply to Claims 1, 3-5, 11-13, and 18-23 are outlined in the rejection above. Lu fails to teach wherein the IL-15Rβ is a subunit domain having less than the whole length 27aa-240aa (Claim 6), specifically wherein the subunit domain is a shortened IL-15Rβ represented by 27-125aa (Claims 7-8). Lu fails to teach the fusion protein having a construct as shown in Fig. 14A (Claim 9) wherein each Fc homodimer comprises, in N-terminal to C-terminal orientation, a IL-15Rβ linked by a cleavable linker to IL-15 linked to IL-15Rα.
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Karow teaches masked IL-15 prodrugs wherein the masking moiety binds to IL-15 until the linker separating the masking moiety and the IL-15 is cleaved in the tumor microenvironment (abstract, Fig. 1A, and paragraph [0011]). The masking moiety can comprise IL-2Rβ (also referred to as CD122) or a fragment thereof and can be selected from SEQ ID NOs: 10, 161-165, 221-226, 261, 826, and 827 (paragraph [0247]). SEQ ID NO: 226 is an IL-15Rβ fragment comprising residues 27-124 of instant SEQ ID NO: 5 (page 356) which reads on Claims 7-8. Karow teaches the masked cytokine construct of instant Fig. 14A in Fig. 7B as shown below. Fig. 7B specifically teaches wherein the cytokine is IL-2, but it is clear from the disclosure that the masked cytokine can instead comprise IL-15 and IL-15 receptors (paragraphs [0011], [0221]-[0224], and [0249]).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to adapt the masked IL-15 cytokine taught by Lu to comprise a IL-15Rβ subunit as taught by Karow and a construct orientation as taught by Karow. Both Lu and Karow teach similar masked IL-15 cytokines comprising the same structural units (IL-15, IL-15Rα, IL-15Rβ, and Fc domain) wherein the IL-15 prodrug is activated in the tumor microenvironment when the linker connecting the masking moiety is cleaved. Karow teaches that a shortened subunit of IL-15Rβ comprising amino acid residues 27-124 can effectively function as the masking moiety and that the masked IL-15 cytokine can comprise the specific orientation as shown above in Fig. 7B. It would have been obvious to substitute equivalents, each of which is taught by the prior art to be useful for the same purpose (IL-15Rβ subunit that masks IL-15; functional masked IL-15 cytokine construct for cancer treatment) (See MPEP 2144.06-II). One of ordinary skill could have applied these known equivalents taught by Karow to the masked IL-15 cytokine of Lu with predictable results.
Claims 1-5, 10-13, and 18-23 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al. US 2020/0392235 (effectively filed June 2019) in view of Ortiz-Sanchez et al. Expert Opin. Biol. Ther. 2008.
The teachings of Lu as they apply to Claims 1, 3-5, 11-13, and 18-23 are outlined in the rejection above. Lu fails to teach wherein the fusion protein further comprises a constant region of light chain and a constant region of heavy chain (Claim 2) specifically in the orientation as shown in Fig. 14B (Claim 10) wherein the IL-15Rα is linked to the N-terminal of the constant light domain and the IL-15Rβ/IL-15 are linked to the N-terminal of the constant heavy domain.
Ortiz-Sanchez teaches that antibody-cytokine fusion proteins can be constructed with a multitude of different orientations wherein the cytokine can be fused at the N- or C-terminal of the full-length antibody (page 613, paragraph 1). Specifically, cytokines can be linked to the N-terminus of the heavy chain or the light chain as shown in Figures 2A(II), 2B(I), and 2B(II). Cytokines can also be linked to the constant heavy domain and the constant light domain (Figure 2B(V)).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to adapt the masked IL-15 construct taught by Lu to comprise the orientation wherein the IL-15Rα is linked to the N-terminal of the constant light domain and the IL-15Rβ/IL-15 are linked to the N-terminal of the constant heavy domain from the teachings of Ortiz-Sanchez. Ortiz-Sanchez teaches that cytokines can be linked to constant heavy and light domains and that cytokines can be linked to the N-terminal of antibodies to form cytokine-antibody fusion proteins. It is well understood in the art that the heavy and light chain variable domains are responsible for binding antigens and the heavy and light chain constant domains comprise the antibody structural framework. It would be obvious to one of ordinary skill that the IL-15/IL-15Rβ could be linked to the N-terminus of the heavy constant domain and the IL-15Rα could be linked to the N-terminus of the light constant domain (or vice versa), and that the masked IL-15 cytokine would perform the same function as when the IL-15/IL-15Rα/IL-15Rβ are linked to the N-terminus of the Fc domain. The IL-15/IL-15Rα/IL-15Rβ complex can be linked to the constant domains instead of the variable domains, because the purpose of the antibody domain is to be a carrier moiety that lengthens half-life (Lu paragraph [0078]) and no antigen binding function is required. Further, as can be seen from Fig. 2 in Ortiz-Sanchez, binding a IL-15/IL-15Rα/IL-15Rβ complex onto each side of the antibody N-terminal is beneficial because it comprises twice the number of cytokines per fusion protein and has spatial separation to avoid potential steric hindrance that may occur when two IL-15/IL-15Rα/IL-15Rβ complexes are bound to the N-terminal Fc domain in closer proximity. One of ordinary skill could combine the teachings of Lu and Ortiz-Sanchez with predictable results.
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.
1. Claims 1, 3-5, 9, 11, and 18-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-8, 10-15, 18, and 20-21 of U.S. Patent No. 12,441,781.
The instant claims recite a fusion protein or fusion protein homodimer complex comprising IL15Rα, IL-15, IL-15Rβ, and an Fc domain wherein the Fc domain is at the C-terminus and the IL-15Rβ is at the N-terminus connected by a cleavable linker (Claim 1). Dependent claims recite: wherein the Fc domain and IL-15 are both human (Claim 3); wherein the IL-15Rα is a whole unit or a subunit (Claims 4-5); wherein the fusion protein has the construct shown in Fig. 14A (Claim 9); wherein one of the non-cleavable linkers comprises GGGGS (Claim 11); wherein the fusion protein is a prodrug (Claim 18); wherein the fusion protein is substantially purified (Claim 19); a polynucleotide encoding the fusion protein and an expression vector comprising the polynucleotide (Claims 20-21); a pharmaceutical composition comprising the fusion protein (Claim 22); and a method of treating hyperplasia, solid tumor, or hematopoietic malignancy by administering the fusion protein (Claim 23).
The patented claims recite a fusion protein comprising an IL-15R, an IL-15, an IL-15Rβ, and an Fc domain wherein the Fc domain is at the C-terminus and the IL-15Rβ is at the N-terminus connected by a cleavable linker in different orientations (Claims 1, 18, and 20-21). The orientation described by Claim 18 is consistent with instant Fig. 14A. Dependent claims recite: wherein the subunit of IL-15R is α (Claims 2-3); wherein the IL-15R is the sushi domain subunit of IL-15Rα (Claim 4); the IL-15 is human (Claim 5); the Fc domain is human (Claim 7); wherein a non-cleavable linker comprises GGGGS (Claim 8); a homodimeric protein comprising the fusion protein (Claim 10); wherein the fusion protein is substantially purified (Claim 11); a polynucleotide encoding the fusion protein and an expression vector comprising the polynucleotide (Claims 12-13); a pharmaceutical composition comprising the fusion protein (Claim 14); and a method of treating hyperplasia, solid tumor, or hematopoietic malignancy by administering the fusion protein (Claim 15). Note, it is understood in the art prior to filing that masked cytokines are considered “prodrugs” because they are inactive until they reach the intended treatment site.
Thus, the instant claims are either anticipated and/or rendered obvious by the Patented claims.
2. Claims 1, 3-5, 9, 11-13, and 18-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 7, 9-10, and 12-18 of copending U.S. App. No. 19/330,743.
The instant claims 1, 3-5, 9, 11, and 18-23 are set forth above. Claim 12 recites wherein the cleavable linker is short, and Claim 13 recites wherein the cleavable linker is long. Note, “short cleavable linker” is defined by the specification as linkers having a length in the range of about 10 to about 20 with one cleavable site, and “long cleavable linker” is defined as linkers having a length in the range of about 20 to about 40 with one or two cleavable sites (paragraph [00155]).
The copending claims recite a fusion protein comprising an IL-15R selected from α or β or γ, an IL-15, an IL-15Rβ, and an Fc domain wherein the IL-15Rβ is connected to the IL-15 by a cleavable linker (Claim 1). Dependent claims recite: wherein the subunit of IL-15R is α (Claim 3); wherein the IL-15R is the sushi domain subunit of IL-15Rα (Claim 4); the IL-15 is human (Claim 5); the Fc domain is human (Claim 7); wherein the cleavable linker is selected from SEQ ID NOs: 10-23 (Claim 9) wherein SEQ ID NO: 10 comprises 15 amino acids and SEQ ID NO: 20 comprises 20 amino acids; wherein a non-cleavable linker comprises GGGGS (Claim 10); a homodimeric protein comprising the fusion protein (Claim 12); wherein the homodimer comprises a monomer from N- to C-terminus of IL-15Rβ, a cleavable linker, IL-15, a linker, IL-15Rα, a linker, and an Fc fragment (Claim 13) which reads on the orientation shown in instant Fig. 14A; wherein the fusion protein is substantially purified (Claim 14); a polynucleotide encoding the fusion protein and an expression vector comprising the polynucleotide (Claims 15-16); a pharmaceutical composition comprising the fusion protein (Claim 17); and a method of treating hyperplasia, solid tumor, or hematopoietic malignancy by administering the fusion protein (Claim 18). Note, it is understood in the art prior to filing that masked cytokines are considered “prodrugs” because they are inactive until they reach the intended treatment site.
Because the copending claims recite the same elements of the instant claims, the instant claims are either anticipated and/or rendered obvious by the copending claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/ Examiner, Art Unit 1675
/STACEY N MACFARLANE/ Examiner, Art Unit 1675