DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of invention Group IV (claim(s) 277-299, drawn to a non-naturally occurring IL-12 variant, comprising: a) a variant IL-12 p35 subunit, wherein the variant IL-12 p35 subunit comprises a first amino acid substitution mutation, wherein the first amino acid substitution is selected from the group consisting of: Y40A, Y40E, Y40G, Y40P, Y40R, Y40S, K170A, K170P,K170T; and b) an IL-12 p40 subunit) in the reply filed on 06/16/2026 is acknowledged.
3. The election without traverse filed 06/16/2026 is acknowledged. Claims 1-268 were previously cancelled. Claim 269-276 and 300-308 are withdrawn. Claims 277-299 are pending and under examination.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted 10/16/2023, 11/14/2023, 01/03/2024, 06/10/2025 and 07/23/2025 and the references cited therein have been considered, unless indicated otherwise.
Specification
5. The use of the term HEK-Blue, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Please review the specification for other Trademarks and correction is required.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6. Claims 277-285, and 287-288 are rejected for being indefinite. The claims provide lab designated mutations, however, do not provide a reference sequence for the IL-12 variant to base the mutations from. One of ordinary skill in the art would not be reasonably apprised to the structure of the IL-12 variant in which the substitutions are being ascribed to. Correction is required.
7. Claim 290 is rejected for being indefinite. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 290 recites the broad recitation “one or more unstructured biodegradable polypeptides (“XTEN”)”. A person of ordinary skill in the art would not be able to determine which polypeptides fall within the scope of the recited “unstructured, biodegradable polypeptide”. Accordingly, claim 290 fails to particularly point out and distinctly claim the subject matter which the inventor regards as the invention, and is rejected as indefinite.
8. Claim 277 recites “”the first amino acid substitution” but does not specify any more substitutions besides the first which renders the claim indefinite. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
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.
8. Claims 277-285, 287-288, 291, 295, and 299 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims are drawn to a non-naturally occurring IL-12 variant, listing first and section amino acid substitutions at various positions. Instant claim 299 specifically is drawn to the non-naturally occurring IL-12 variant of claim 277, wherein the variant IL-12 p35 subunit comprises one or more additional amino acid substitutions.
The specification teaches the variant IL-12 p35 subunit comprises four or more amino acid substitutions selected from the group including: Y40A, T43A, D126A, P127A, R129A, K168A, and K170A. [0011] In a further embodiment and in accordance with the above, the variant IL-12 p35 subunit comprises five or more amino acid substitutions selected from the group including: Y40A, T43A, D126A, P127A, R129A, K168A, and K170A. [0012] In a further embodiment and in accordance with the above, the variant IL-12 p35 subunit comprises six or more amino acid substitutions selected from the group including: Y40A, T43A, D126A, P127A, R129A, K168A, and K170A. [0013] In a further embodiment and in accordance with the above, the variant IL-12 p35 subunit comprises seven or more amino acid substitutions selected from the group including: Y40A, T43A, D126A, P127A, R129A, K168A, and K170A. The specification further teaches variant IL-12 p35 subunit comprises a substitution mutation at amino acid residue R129. In some further embodiments, the substitution mutation at amino acid residue R129 is selected from the group including: R129C, R129D, R129E, R129F, R129G, R129H, R129I, R129K, R129L, R129M, R129N, R129P, R129Q, R129S, R129T, R129V, R129W, and R129Y. The specifications teaches the variant IL-12 p35 subunit comprises a first substitution mutation selected from the group including: Y40A, Y40C, Y40D, Y40E, Y40G, Y40K, Y40N, Y40P, Y40Q, Y40R, Y40S, and Y40T. [0033] In a further embodiment and in accordance with the above, the variant IL-12 p35 subunit further comprises a second substitution mutation. [0034] In a further embodiment and in accordance with the above, the second substitution mutation is selected from the group including: D126A, D126C, D126E, D126F, D126G, D126I, D126K, D126L, D126M, D126N, D126P, D126Q, D126R, D126S, D126T, D126V, D126W, P127A, P127C, P127D, P127E, P127F, P127G, P127H, P127K, P127M, P127N, P127Q, P127R, P127S, R129A, R129C, R129D, R129E, R129F, R129G, R129H, R129I, R129K, R129L, R129M, R129N, R129P, R129Q, R129S, R129T, R129V, R129W, R129Y, K168A, K168C, K168D, K168E, K168F, K168G, K168H, K168I, K168L, K168M, K168N, K168P, K168Q, K168S, K168T, K168W, K168Y, K170A, K170C, K170D, K170E, K170G, K170I, K170M, K170P, K170S, K170T, K170V, and K170W.
The claims lack written description because the claims recite generic and incompletely described non-naturally occurring IL-12 variant. One of ordinary skill in the art would not be reasonably apprised of the structure of the IL-12 variant without adequate descriptions of its component parts or overall makeup. The generically claimed IL-21 variant with various mutations 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 fusion polypeptides as recited in the claims, as written. For instance, without knowing the entire structure of the claimed IL-12 variant, one would not be able to adequately describe the claimed IL-12 variant. The claims state that the IL-12 variant comprises a IL-12p35 subunit and IL-12p40 subunit joined by a linker; however, this definition provides no name for the encompassed IL-12 variant or the specific structure of the IL-12 variant having the recited function. The generic recitation of these subunits is not a description of the IL-12 variant itself. The claims teach that the IL-12 variant comprises a linker between the subunits. However, this is not a description of the linker sequence itself. Thus, the claims identify the IL-12 variant solely by their function and/or partial structure.
Furthermore the claims recite a non-naturally occurring IL-12 variant comprising a variant IL-12p35 subunit and p40 subunit without specifying the species of origin of the IL-12. The claims encompasses IL-12 variant derived from the IL-12 of any species, including but not limited to human, murine and other mammalian IL-12. The specification, however, describes only human IL-12 p35 and p40 subunits. The specification does not provide a representative number of species falling with the claim genus of IL-12 variant, nor does it disclose structure features commons to the members of the genus across species such that one of ordinary skill in the art would recognize that the inventor was in possession of IL-12 variant derived from species other than human.
Accordingly, the specification does not define any structural features commonly possessed by members of the genus, because while the description of an ability of the claimed agent may generically describe the agent’s function, it does not describe the agent itself. A definition by function does not suffice to define the genus because it is only an indication of what the agent does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of agents is highly variable (i.e., each fusion polypeptide would necessarily have a unique structure; see MPEP
2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed agonists have no correlation between their structure and function and the specification fails to provide adequate written description to support the genus of fusion polypeptides encompassed by the claims.
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 described IL-12 variant comprising the subunits, 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 IL-12 variant and encompass a vast genus of IL-12 variant comprising any IL-12p35 subunit, any IL-12p40 subunit and any linker. 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. Given the vast number of agents that are encompassed by the claims, the disclosure of a few species is not sufficiently representative of the broad genus of agonists encompassed by the claims. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Additionally, regarding instant claim 299 which states the IL-21p35 subunit comprises one or more additional amino acid substitution, applicants have not shown possession of a representative number of species that have the claimed function(s).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed agents, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601,1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2dl961,1966 (1997); In re Gosteli, 872 F.2dl008,1012,10 USPQ2dl614, 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.
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. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) 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 moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). 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 fall (See page 321). 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).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside 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 Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al. and Burgess et al. but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted.
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 polypeptides. 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 polypeptides 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 fusion protein such that one would be able to distinguish it from the fusion polypeptides 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 fusion polypeptides as claimed.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The 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 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and 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. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 102
(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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
9. Claim 277, 286, 290, 295 and 296 is rejected under 35 U.S.C. 102(a)(2) as being unpatentable over Lu, et al. (WO 2022/155263 A2, published 21 July 2022, effectively filed 12 January 2021).
The instant claims are drawn to a non-naturally occurring IL-12 variant, comprising: a) a variant IL-12 p35 subunit, wherein the variant IL-12 p35 subunit comprises a first amino acid substitution mutation, wherein the first amino acid substitution is selected from the group consisting of: Y40A, Y40E, Y40G, Y40P, Y40R, Y40S, K170A, K170P,K170T; and b) an IL-12 p40 subunit
Lu, et al. teach a non-naturally occurring IL-12 variant comprising IL-12p35 subunit of SEQ ID NO: 6 with the substitution Y40A, and an IL-12p40 subunit (paragraph 8-9 and 88-90).
Instant SEQ ID NO: 24 is 100% match with SEQ ID NO: 6 of Lu, et al. with the Y40A substitution as taught by Lu, et al.
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Lu, et al. teach the IL-12 polypeptide which included the Y40A substituted variant, is operably linked to a carrier, wherein the carrier is selected from a PEG molecule or an albumin molecule (paragraph 12 and 96). Thus, the limitation of instant claim 290 is anticipated.
Lu, et al. teach the C-terminus of the IL-12p35 subunit is covalently attached to the N-terminus of the variant IL-12p35 subunit (Paragraph 12, 38, 41 and figure 8) and Lu, et al. teach p35 subunit is fused to the p40 subunit through a peptide linker comprising GGGGS (paragraph 12), which is same sequence as instant SEQ ID NO: 14. Therefore, Lu, et al anticipate claim 295 and 296.
10. Claims 277 and 286 are rejected under 35 U.S.C. 102(a)(2) as being unpatentable over Wang, et al (US 2023/0035308 A1, filed 1 July 2022).
The instant claims are drawn to a non-naturally occurring IL-12 variant, comprising: a) a variant IL-12 p35 subunit, wherein the variant IL-12 p35 subunit comprises a first amino acid substitution mutation, wherein the first amino acid substitution is selected from the group consisting of: Y40A, Y40E, Y40G, Y40P, Y40R, Y40S, K170A, K170P,K170T; and b) an IL-12 p40 subunit.
Wang, et al. teach a non-naturally occurring IL-12 variant comprising a variant p35 bearing K170A and an IL-12p40 subunit (paragraph 16 and figure 6a/10a-10b) which is 100% identical to instant SEQ ID NO 103.
Instant SEQ ID NO 103 is 100% identical to SEQ ID NO 98 of Wang, et al. Thus, instant claims 277 and 286 are anticipated.
Query Match 100.0%; Score 1012; Length 197;
Best Local Similarity 100.0%;
Matches 197; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 RNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTV 60
Qy 61 EACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMN 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 EACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMN 120
Qy 121 AKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTAIKLCILLHAF 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTAIKLCILLHAF 180
Qy 181 RIRAVTIDRVMSYLNAS 197
|||||||||||||||||
Db 181 RIRAVTIDRVMSYLNAS 197
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.
11. Claim 277, 286, 287, 288, 290, 295 and 296 are rejected under 35 U.S.C. 103 as being unpatentable over Lu, et al. (WO 2022/155263 A2, published 21 July 2022, effectively filed 12 January 2021).in view of Bernett, et al. (US 2020/0216509 A1, published 9 July 2020).
The instant claims are drawn to a non-naturally occurring IL-12 variant, comprising: a) a variant IL-12 p35 subunit, wherein the variant IL-12 p35 subunit comprises a first amino acid substitution mutation, wherein the first amino acid substitution is selected from the group consisting of: Y40A, Y40E, Y40G, Y40P, Y40R, Y40S, K170A, K170P,K170T; and b) an IL-12 p40 subunit. Lu, et al. teach a non-naturally occurring IL-12 variant comprising IL-12p35 subunit of SEQ ID NO: 6 with the substitution Y40A, and an IL-12p40 subunit (paragraph 8-9 and 88-90). Instant SEQ ID NO: 24 is 100% match with SEQ ID NO: 6 of Lu, et al. with the Y40A substitution as taught by Lu, et al. Lu, et al. teach the IL-12 polypeptide which included the Y40A substituted variant, is operably linked to a carrier, wherein the carrier is selected from a PEG molecule or an albumin molecule (paragraph 12 and 96). Thus, the limitation of instant claim 290 is anticipated. Lu, et al. teach the C-terminus of the IL-12p35 subunit is covalently attached to the N-terminus of the variant IL-12p35 subunit (Paragraph 12, 38, 41 and figure 8) and Lu, et al. teach p35 subunit is fused to the p40 subunit through a peptide linker comprising GGGGS (paragraph 12), which is same sequence as instant SEQ ID NO: 14. Therefore, Lu, et al anticipate claim 295 and 296.
Lu, et al. does not teach the IL-12p35 further comprises a C74S substation and does not teach the IL-12p40 subunit does not contain C177s, C252S or C177s/C252S mutation.
However, Bernett, et al. teach Bernett, et al. teach a non-naturally occurring IL-12 variant comprising a variant p35 subunit and a variant Il-12p40 subunit with the substitution C252S (paragraph 7) and further teach amino acid modification of IL-12p35 at position C74 (paragraph 33).
It would have been obvious to one of ordinary skill in the art before the effective filing to introduce the C252S substitution taught by Bernett, et al and the modification at C74 to a serine into the IL-12p40 and p34 subunit. A skilled artisan would have been motivated to remove the free cysteine and improve potency (paragraph 488), as taught by Bernett, et al. The use of a known technique to improve similar products in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
12. Claim 277, 286, 289, 290, 295 and 296 are rejected under 35 U.S.C. 103 as being unpatentable over Lu, et al. (WO 2022/155263 A2, published 21 July 2022, effectively filed 12 January 2021) in view of Webster, et al. (US 2007/0154453 A1, published 5 July 2027).
The instant claims are drawn to a non-naturally occurring IL-12 variant, comprising: a) a variant IL-12 p35 subunit, wherein the variant IL-12 p35 subunit comprises a first amino acid substitution mutation, wherein the first amino acid substitution is selected from the group consisting of: Y40A, Y40E, Y40G, Y40P, Y40R, Y40S, K170A, K170P,K170T; and b) an IL-12 p40 subunit. Lu, et al. teach a non-naturally occurring IL-12 variant comprising IL-12p35 subunit of SEQ ID NO: 6 with the substitution Y40A, and an IL-12p40 subunit (paragraph 8-9 and 88-90). Instant SEQ ID NO: 24 is 100% match with SEQ ID NO: 6 of Lu, et al. with the Y40A substitution as taught by Lu, et al. Lu, et al. teach the IL-12 polypeptide which included the Y40A substituted variant, is operably linked to a carrier, wherein the carrier is selected from a PEG molecule or an albumin molecule (paragraph 12 and 96). Thus, the limitation of instant claim 290 is anticipated. Lu, et al. teach the C-terminus of the IL-12p35 subunit is covalently attached to the N-terminus of the variant IL-12p35 subunit (Paragraph 12, 38, 41 and figure 8) and Lu, et al. teach p35 subunit is fused to the p40 subunit through a peptide linker comprising GGGGS (paragraph 12), which is same sequence as instant SEQ ID NO: 14. Therefore, Lu, et al anticipate claim 295 and 296.
Lu, et al. does not teach the specific sequence of the IL-12p40 subunit as taught in instant claim 289.
However, Webster, et al. teach SEQ ID NO: 2, which is a 100% identical sequence to instant SEQ ID NO: 4.
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One of ordinary skill in the art would have motivated to use the IL-12p40 subunit of Webster, incorporated in the IL-12 of Lu, et al. because Webster, et al. teach the IL-12p40 variant improves stability improved to wild-type IL-12p40 subunits. Applying a known technique to a known product ready for improvement to yield predictable results is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, D.).
13. Claim 277, 286, 290, 291, 292 295 and 296 are rejected under 35 U.S.C. 103 as being unpatentable over Lu, et al. (WO 2022/155263 A2, published 21 July 2022, effectively filed 12 January 2021) in view of Marcus, et al. (US 11,129,883 B2, published 28 September 2021)
The instant claims are drawn to a non-naturally occurring IL-12 variant, comprising: a) a variant IL-12 p35 subunit, wherein the variant IL-12 p35 subunit comprises a first amino acid substitution mutation, wherein the first amino acid substitution is selected from the group consisting of: Y40A, Y40E, Y40G, Y40P, Y40R, Y40S, K170A, K170P,K170T; and b) an IL-12 p40 subunit. Lu, et al. teach a non-naturally occurring IL-12 variant comprising IL-12p35 subunit of SEQ ID NO: 6 with the substitution Y40A, and an IL-12p40 subunit (paragraph 8-9 and 88-90). Instant SEQ ID NO: 24 is 100% match with SEQ ID NO: 6 of Lu, et al. with the Y40A substitution as taught by Lu, et al. Lu, et al. teach the IL-12 polypeptide which included the Y40A substituted variant, is operably linked to a carrier, wherein the carrier is selected from a PEG molecule or an albumin molecule (paragraph 12 and 96). Thus, the limitation of instant claim 290 is anticipated. Lu, et al. teach the C-terminus of the IL-12p35 subunit is covalently attached to the N-terminus of the variant IL-12p35 subunit (Paragraph 12, 38, 41 and figure 8) and Lu, et al. teach p35 subunit is fused to the p40 subunit through a peptide linker comprising GGGGS (paragraph 12), which is same sequence as instant SEQ ID NO: 14. Therefore, Lu, et al anticipate claim 295 and 296.
Lu, et al. does not teach the C-terminus of the IL-12 p35 subunit is attached to the N-terminus of the IL-12p40 subunit with the linker of instant claim 291.
However, Marcus, et al. teach the IL-12 may comprise either the C-terminus of p40 linked to the N-terminus of p35 or the C-terminus of p35 linked to the N-terminus of p40. It would have been obvious to one of ordinary skill in the art before the effective filing date to arrange Lu’s variant IL-12 in the orientation of instant claim 21, as Marcus, et al. teach both orientations as known in the art for construction the IL-12. Lu, et al. teach p35 subunit is fused to the p40 subunit through a peptide linker comprising GGGGS (paragraph 12), which is same sequence as instant SEQ ID NO: 14. Thus, instant claim 291 and 292 is anticipated. The use of a known technique to improve similar products in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
14. Claims 293, 294, 297 and 298 is rejected under 35 U.S.C. 103 as being unpatentable over Lu, et al. and Marcus, et al as applied to claims 277, 286, 290, 291, 292, 295 and 296 and in further view of Lupardus, et al. (US 2024/0132562 A1, priority filing date 10 October 2021).
Instant claim 293 is drawn to the non-naturally occurring IL-12 variant of claim 291, wherein the non-naturally occurring IL-12 variant further comprises a Fc domain, wherein the Fc domain comprises one or more amino acid sequences selected from the group consisting of: SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, and the Fc domain is fused to the variant IL-12 p35 subunit or the IL-12 p40 subunit
The teachings of Lu, et al. and Marcus, et al. are above
Lu, et al. and Marcus, et al do not teach sequences of the Fc domain of instant claim 293, 297 and 298.
However, Lupardus, et al. teach Fc fusion conjugates have been shown to increase the systemic half-life of biopharmaceuticals, and thus the biopharmaceutical product can require less frequent administration. Lupardus further teach Fc domains are linked to p35 and p40 of IL-12 (paragraph 17) with a linker (paragraph 239). Lupardus, et al. teach the Fc domain of SEQ ID NO: 169, which is 100% identical to the Fc domain of instant SEQ ID NO: 12.
Query Match 100.0%; Score 1264; Length 559;
Best Local Similarity 100.0%;
Matches 231; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EPKSSDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 329 EPKSSDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF 388
Qy 61 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 389 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKT 448
Qy 121 ISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTP 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 449 ISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTP 508
Qy 181 PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 231
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 509 PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 559
One of ordinary skill in the art could reasonably incorporate the Fc domain taught by Lupardus, et al. to the Lu, et al. and Marcus, as Lu, et al. teach Fc domain linked to the IL-12p35 or p40 subunit (paragraph 62). Marcus, et al. provide C-terminus of the variant IL-12p35 subunit attached the N-terminus of the IL-12p40 subunit and Lu, et al. teach the C-terminus of the IL-12p35 subunit is covalently attached to the N-terminus of the variant IL-12p35 subunit (Paragraph 12, 38, 41 and figure 8). Thus, instant claim 293, 294, 297 and 298. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.).
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.
15. Claims 277, 279, 281, 282, 286, 287, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 6, 7, 18, 152 and 302 of copending Application No. 19033268 (reference application).
The instant claims are drawn to a IL-12 variant that comprises an IL-12p35 subunit, IL-12p40 subunit, a linker and a Fc domain. This constitutes the structure of a IL-23 Fc fusion protein.
Copending application ‘268 teaches an IL-12 Fc fusion protein, comprising:(a) a first monomer comprising, from N-terminus to C-terminus: (i) a first IL-12 subunit domain, (ii) a first domain linker, (iii) a second IL-12 subunit domain, (iv) a second domain linker, and (v) a first Fe domain, wherein:(1) the first IL-12 subunit domain comprises an IL-12 p40 subunit domain and the second IL-12 subunit domain comprises a variant IL-12 p35 subunit domain or the first IL-12 subunit domain comprises a variant IL-12 p35 subunit domain and the second IL-12 subunit domain comprises an IL-12 p40 subunit domain, and(2) the variant IL-12 p35 subunit domain comprises a set of amino acid substitutions selected from the group consisting of: (a) Y40S/K170A, (b) Y40S/K170T, (c) Y40P/K168A, (d) Y40P/K170A, and (e) Y40E/K170A; (b) a second monomer comprising, from N-terminus to C-terminus: (i) a variable heavy (VH) domain, (ii) a constant heavy (CH1) domain, and (iii) a second Fe domain; and (c) a third monomer comprising, from N-terminus to C-terminus: (i) a variable light (VL) domain, and (ii) a constant light (CL) domain, wherein the VH domain and VL domain form an antigen binding domain (ABD) that binds a target antigen.
The following sequences are identical and constitute the structure of IL-12p35 subunit, IL-12p40 subunit, a linker and a Fc domain:
Copending application ‘268 teaches in claim 2, 5, 6, 7, 18, and 402, various SEQ ID NOs associated with the invention. Instant SEQ ID NO: 12 is 100% identical with copending SEQ ID NO: 29, 27, 87 and 90. Instant SEQ ID NO: 13 is 100% identical with copending SEQ ID NO: 30, 89, 51, 37, 38, 50, 49, 52, and 28. . Instant SEQ ID NO: 17 is 100% identical with copending SEQ ID NO: 34. Instant SEQ ID NO: 88 is 100% identical with copending SEQ ID NO: 23. . Instant SEQ ID NO: 89 is 100% identical with copending SEQ ID NO: 24. Instant SEQ ID NO: 258 is 100% identical with copending SEQ ID NO: 17, 89 and 48. Instant SEQ ID NO: 264 is 100% identical with copending SEQ ID NO: 20 and 49. Instant SEQ ID NO: 266 is 100% identical with copending SEQ ID NO: 19 and 50.
These sequences coincide with the exact structure and function of the invention. Thus, claims 277, 279, 281, 282, 286, 287, 289-298 are provisionally rejected of the copending application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
16. No claims are allowed.
Conclusion
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Syed J Abbas whose telephone number is (571)272-0015. The examiner can normally be reached M-Th, 9:00AM-4:00PM.
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/SYED J ABBAS/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
Prosecution Insights