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 .
Election/Restrictions
Applicant’s election without traverse of Group II and species of N-terminal polypeptide modification of acetylation and of C-terminal polypeptide modification of amidation in the reply filed on 03/05/2026 is acknowledged.
Specification
Title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested:
Recombinant Polypeptides Comprising an IL-17RB Inactivation Site (IRIS), Conjugates and Uses Thereof.
Disclosure
The disclosure is objected to because of the following informalities: In, [0033] on p. 8, line 3, “only has” should be “only have”. In line 2 of [0037], “herein to refer means” apparently should be ‘herein to refer to a means”. In [0106], line 1, “fortumorigenesis” should be “for tumorigenesis”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3 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 a recombinant polypeptide comprising 2 to 20 copies of an IL-17RB inactivation site (IRIS) consisting of an amino acid sequence identical to SEQ ID NO:2 or another naturally occurring IL-17RB IRIS sequence and the recombinant protein is conjugated to a vaccine carrier protein, does not reasonably provide enablement for wherein the IRIS is not naturally occurring and wherein the recombinant protein is not conjugated to a vaccine carrier protein. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 is drawn to a recombinant polypeptide comprising 2 to 20 copies of an IL-17TB inactivation site (IRIS) having an amino acid sequence at least 85% identical to SEQ ID NO:2, wherein each copy of the IRIS sequence is serially connected to each other. The claim has no limitation related to the connection other than that the connection is serial. There is no structural limitation for the connection itself. There is no structural limitation for the IRIS beyond being 85% identical to SEQ ID NO:2. The recombinant polypeptide has no recited function. The invention as disclosed relates to the ability to block IL-17RB activity, e.g., binding to its ligands, to reduce tumor growth and/or metastases (Example 4). The only working example of the recombinant polypeptide is wherein it is conjugated to a carrier (see [0045]-[0059] and Examples 1-4), the carrier being CRM197, and linked through a succinimidyl 3-(bromoacetamido) propionate (SBAP; e.g., [0092]). Further, multimers of the IRIS sequence are separated by a Gly Gly linker (see, e.g., SEQ ID NO:4 and 6). These facts raise two enablement issues. One is that it reasonably appears that on its own, the IRIS fragment of human IL-17RB (SEQ ID NO:2), either singly or multiple copies thereof that are serially linked, are poorly immunogenic and have shown no activity alone. That is, for the disclosed treatment of cancer, which all treatment in the specification is directed (e.g., [0018]-[0019] and Example 4), the IRIS acts as a vaccine with the conjugated carrier that makes it sufficiently immunogenic (Fig. 1). The invention is described as ([0040]):
The present disclosure is based, at least in part, on the discovery that blocking the IL-17RB inactivation site (IRIS) epitope may interrupt IL-17RB signalling, thus prevents the cancer cells from spreading and/or growing. Based on this discovery, the present disclosure aims at providing a novel anti-cancer strategy, in which a cancer vaccine against the IRIS epitope is developed, which may trigger a host's immune responses to block the IRIS epitope and prevent cancers, especially the IRIS-overexpressed cancers, from spreading and/or growing.
Malito et al, (Proc. Natl. Acad. Sci. USA, 2012 Mar 19;109(14):5229-5234, p. 5229, col. 1, third paragraph) teaches that carrier CRM197 (cross-reactive material197) is naturally nontoxic and enzymatically inactive. It is reported that “Vaccines containing CRM197 as a carrier protein have been successfully used to immunize hundreds of millions of children,” including for bacterial and viral infections (p. 5229, paragraph bridging pp. 1-2). The specification presents suitable carrier proteins in [0047]. Claim 3 specifies the N-terminus of the recombinant polypeptide is acetylated, and according to the specification in [0049] the acetyl, e.g., bromoacetyl or iodoacetyl, is linked to the sulfhydryl group of the carrier, for example linked to SBAP (succinimidyl 3-(bromoacetamido) propionate). When mice were immunized only with CRM197 there was no detectable reactivity, but immunization with the CRM197-SBAP-hIRIS2 induced a strong immune response against recombinant IL-17RB extracellular domain (ECD) ([0086]). If the claimed recombinant protein is not used in a vaccine format, the skilled artisan would not know how to use it. There is no guidance or direction for using it for other than as a vaccine. The prior art does not teach the use of the IL-17RB IRIS specifically. It does teach wherein the whole IL-17RB ECD was used to produce antibodies through immunization and a resulting monoclonal antibody, D9, blocked tumor metastasis and improved survival in a mouse xenograft model (Wu et al., J. Exp. Med. 212 (3):333–349, 2015, Fig. 7, p. 346, col. 1, second paragraph, and col. 2, fourth full paragraph). There is no teaching of using multiples of regions larger than the IRIS sequence which are serially connected. The activity of antibody D9 is consistent with a successful vaccine against the IL-17RB IRIS as shown by the inventors. Therefore, while the invention is not enabled for a nondescript recombinant polypeptide comprising 2-20 IL-17RB IRISs, it is wherein the IRISs, without more of the IL-17RB sequence to which antibodies not binding the IRIS could be produced, are conjugated to a carrier protein suitable for a vaccine. There is no reasonable expectation that a protein of SEQ ID NO:2 or serial repeats thereof could be used alone as an immunogen in the absence of conjugation to a carrier protein.
The second enablement issue is the broad structure of the recited serially linked sequence--one comprising (having) at least 85% identical to SEQ ID NO:2. The respective mouse and human IL-17RB IRIS of instant SEQ ID NO:1 and 2 are less than 80% identical. The IRIS fragment is only 13 amino acids and appears to be poorly immunogenic as discussed above. A peptide 85% identical to SEQ ID NO:2 allows for up to 2 amino acid changes (substitutions, deletions or additions) and encompasses over 30,000 possible sequences. Even if only a single amino acid is changed (90% identity), then there are over 250 possible sequences. In order to function in a vaccine, the IRIS must be an antigen to which an antibody produced by an immune response to the vaccine binds, thereby inhibiting IL-17RB activity. If the IRIS sequence does not produce antibodies with sufficient specificity to bind the innate IRIS antigen of the animal to which the vaccine is administered, then it cannot be used. As a result, the IRIS component of the vaccine must be identical or sufficiently identical to the amino acid sequence of SEQ ID NO:2 for a human vaccine (or SEQ ID NO:1 for a mouse). Janeway, C. (2001) Immunobiology: The Immune System in Health and Disease, 5th Edition (New York:Garland Pub.) teaches (section 3-8) that, “[A]ntibodies raised against peptides of a protein or against synthetic peptides corresponding to part of its sequence are occasionally found to bind to the natural folded protein. This makes it possible, in some cases, to use synthetic peptides in vaccines that aim at raising antibodies against a pathogen protein.” It is discussed that a short peptide, e.g., the IRIS of IL-17RB, to which such antibodies bind is generally in the pocket or groove between the V domains of the heavy and light chains (Fig. 3.9, left and center panels, paragraph 2 of section 3-7). Such binding requires specificity. The skilled artisan would not reasonably expect antibodies binding peptides not identical to the IRIS of IL-17RB would also bind the natural folded protein, which is critical for the antibody to function as an anticancer agent or even as a diagnostic agent. Therefore, an IRIS that does not have the sequence from a natural IL-17RB protein is not enabled because the skilled artisan would not reasonably expect that it could be successfully used in a vaccine to produce antibodies that bind the natural IL-17RB protein.
For the reasons discussed above and including the breadth of the structure of the recombinant polypeptide and particularly the sequence 85% identical to SEQ ID NO:2 or comprising an amino acid sequence at least 85% identical to SEQ ID NO:2, the lack of functional limitation in the claims and only disclosed use as part of a vaccine wherein the IRIS sequence is conjugated to a carrier (CRM197), the support in the vaccine prior art for the need of a carrier for weakly immunogenic peptides, the working examples limited only to wherein the IRIS fragment of IL-17RB or serially connected fragments are conjugated to CRM197, and the complexity and unpredictability of producing an immune response by vaccination to yield a therapeutic effect, it would have required undue experimentation to use the invention commensurate in scope with the claims.
Claims 1-3 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 specification discloses human IL-17RB inactivation site (IRIS) sequence of SEQ ID NO:2 and serially connected IRIS sequences linked by Gly Gly. Also disclosed is a conjugate of the serially connected IRIS sequences comprising a carrier protein to which the connected IRIS sequences are linked. The IRIS of SEQ ID NO:2 serially connected by Gly Gly to additional IRIS sequence of SEQ ID NO:2 and linked to a carrier meets the written description provision of 35 USC 112, first paragraph. However, the claims are directed to or encompass sequences 85% identical to SEQ ID NO:2, wherein serially connected IRIS sequences either are connected without a linker or with a rigid or long linker. None of these sequences or the polypeptide comprising them in the absence of conjugation to a carrier meets the written description provision of 35 USC 112(a).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention 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).
There are two main issues related to a lack of written description for the claims. First, the only disclosed serially connected sequences are naturally occurring IRIS sequences of mouse (SEQ ID NO:1) or human (SEQ ID NO:2). There is no disclosure of non-naturally occurring sequences or of larger fragments of IL-17RB being serially connected. Because claim 1 uses the language of the recombinant polypeptide comprising 2 to 20 copies of an IL-17RB IRIS sequence…. (emphasis added), this is “open language” and may include more than the IRIS sequence of IL-17RB, for example it may include the full-length receptor or the transmembrane domain. However, there is no disclosure of a recombinant polypeptide comprising serially connected any IL-17RB sequence other than the IRIS sequence. Further, even though claim 1 encompasses sequences 85% identical to SEQ ID NO:2, there is no non-identical sequence that was used nor could the skilled artisan immediately envisage sequences other than a naturally occurring IL-17RB IRIS sequence, particularly in the context of serially connected sequences and/or conjugated to a carrier protein. Because an invention has to have an activity, i.e., be able to be used, explicitly recited or inherently encompassed, and because the only disclosed IRISs are naturally occurring and can be used in a vaccine context, sequences not identical thereto do not have written description. Janeway, C. (2001) Immunobiology: The Immune System in Health and Disease, 5th Edition (New York:Garland Pub.) teaches (section 3-8) that, “[A]ntibodies raised against peptides of a protein or against synthetic peptides corresponding to part of its sequence are occasionally found to bind to the natural folded protein. This makes it possible, in some cases, to use synthetic peptides in vaccines that aim at raising antibodies against a pathogen protein.” It is discussed that a short peptide, e.g., the IRIS of IL-17RB, to which such antibodies bind is generally in the pocket or groove between the V domains of the heavy and light chains (Fig. 3.9, left and center panels, paragraph 2 of section 3-7). Such binding requires specificity.
Second, the only disclosed serially connected IRIS sequences comprised by a recombinant protein as set forth in claim 1 are connected by a Gly Gly linker, which is a short flexible linker. It reasonably appears that in order for serially connected IRIS peptides, there must be a flexible linker between each IRIS sequence. The specification discloses only serial linkage of IRIS peptides with a connecting Gly Gly linker between each as exemplified by SEQ ID NO:6, 8, etc. (and [0091]). Chichili et al. (Prot. Sci. 22:153-167, 2013, p. 153, col. 2) discusses that interdomain linkers within proteins generally comprise Pro, Arg, Phe, Thr, Glu and Gln, which act as rigid spacers, while preventing unfavorable interactions between the domains. On the other hand, other preferred natural linkers are Thr, Ser, Gly and Ala, which provide flexibility. “Poly-Gly and Gly-rich linkers can be considered as independent units and do not affect the function of the individual proteins to which they attach. The fused proteins behave independently, such that the single chained proteins can perform the combined function of fused partners.23,24” (p.154, col. 2, col. 2, start of second paragraph) Therefore, it reasonably appears that a short flexible linker connecting IRIS sequences is required for presentation suitable for an immune reaction based on the IRIS sequences. The only disclosed IRIS connecting linker is Gly Gly.
A broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The specification does not disclose a representative number of species by actual reduction to practice or disclosure of relevant identifying characteristics sufficient to show the inventors were in possession of the claimed genus. “Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions 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. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) ” (MPEP § 2163(II)(3)(a)(ii)) In this instance, the disclosure is directed to a vaccine raising an immune response to the IRIS. Neither the prior art nor specification support the use of a non-naturally occurring IRIS. Nor is there description or support in the prior art for a series of repeating IRIS peptides in the absence of a linker between each connected IRIS unit. The only structure-function correlation is limited to that of the 13 amino acid mouse or human IRIS peptide connected by Gly Gly to another such IRIS peptide that when conjugated to a carrier protein by a linker can function as a vaccine to raise antibodies to the IRIS of IL-17RB.
Therefore, only a recombinant protein comprising 2 to 20 copies of the IL-17RB IRIS of SEQ ID NO:2, wherein the IRIS peptide sequence is serially connected by Gly Gly to the same IRIS sequence, but not the full breadth of the claim, meets the written description provision of 35 U.S.C. § 112(a). 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).
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
June 16, 2026
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