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 with traverse of Group I (claims 1-14) and species: NKSNMCESSKEALAENNLNLPK (SEQ ID NO:4) and formula (I): (AESSKEALAENNLNLPKC)-GMB]-CRM197, the peptide part of this conjugate is SEQ ID NO:20), in the reply filed on 2/17/2026 is acknowledged. The traversal is on the grounds that it is improper to require restriction within a single claim, restriction is only permissible between different claims, and all of the claims share a common technical feature. Applicants’ arguments have been considered but are non-persuasive because the immune conjugate of Group I lacks a special technical feature, which defines a contribution over the prior art. The claimed immune conjugate fails to recite a special technical feature absent in the prior art because Lucille Desallais et al (2016) describes a conjugate comprising a peptide derived from human interleukin-6 (hIS200). This peptide corresponds to a region involved in the interaction between interleukin-6 and its receptor IL-6Rα. hIS200 comprises the sequence 78-94 of human interleukin-6: Acetyl + C78 ESSKEALAENNLNLPK94CY. This peptide is cyclized by the formation of intramolecular disulfide bridges between the cysteine residues and it is coupled to KLH (Keyhole limpet haemocyanin) via bis(diazo)benzidine (BDB). Since the claimed invention lacks a special technical feature, the other claimed inventions cannot share a special technical feature with the first claimed invention. Furthermore, contrary to Applicant’s arguments, claim 1 recites “….at least one polypeptide having at most 100 amino acids comprising a sequence of 5 to 50 amino acids of interleukin 6 (IL-6) or interleukin 6 receptor (IL-6R), or a variant sequence having at least 75% identity with the sequence of 5 to 50 amino acids of IL-6 or IL-6R”. In addition, IL-6 and IL-6R are very disparate in amino acid sequence and immunogenic conjugates of these proteins would be separate and patentably distinct. Also, there is absence of a recitation of the amino acid sequence for immunoconjugate comprising IL-6 and the immunoconjugate comprising IL-6R in the independent claim, and in the absence of recitation of the amino acid sequence of IL-6 in the immunoconjugate, the product of Group I lacks a special technical feature over the prior art reference . Therefore, Applicants are arguing limitations absent from the claims.
The test for propriety of restriction is not whether the inventions are related but rather whether they are distinct and whether it would impose a burden on the examiner to search and examine multiple inventions in a single invention. The claimed methods are independent and distinct, each from the other, requiring separate searches, which would be unduly burdensome. Furthermore, separate search terms would be required for searching the literature, e.g. a search of the literature for a method of treatment of an autoimmune bullous disease would not necessarily reveal art for an association of the method with a kit or with the polypeptide to be administered.
The Groups as delineated in the restriction requirement of 10/15/2025 are patentably distinct one from the other such that each invention could, by itself, in principle, support its own separate patent (as shown by the arguments put forth in the written restriction requirement).
The requirement is still deemed proper and is therefore made FINAL.
Claims 8-10, 13-15 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Amended claim 5, 7, (2/17/2026), and previously presented claims 1-4, and 11-12 are under consideration by the Examiner.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 6/30/2022, is in compliance with the provisions of 37 CFR 1.97 and has been considered by the examiner.
Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section”.
Claim Rejections - 35 USC § 112(a), lack of written description
4. 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.
4a. Claims 1-7, 11-12, 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 pre-AIA the inventors, 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.
Independent claim 1 recites “an immunogenic conjugate comprising: - a carrier protein and - at least one polypeptide having at most 100 amino acids comprising a sequence of 5 to 50 amino acids of interleukin 6 (IL-6) or a variant sequence having at least 75% identity with the sequence of 5 to 50 amino acids of IL-6, wherein the polypeptide is covalently linked to the carrier protein and the carrier protein is a non-toxic mutant diphtheria toxin”. Dependent claim 2 recites that in the immunogenic conjugate “the carrier protein is CRM197”. Dependent claim 3 recites that “the polypeptide comprises a 7 to 35 amino acid sequence of IL-6 or a variant sequence having at least 90% identity to the 7 to 35 amino acid sequence of IL- 6”.
The claims as recited would represent a large pool of variant peptides that must have similar functional activity to IL-6. A 75% identity, for example, in the IL-6 polypeptide that is “50 amino acids” translates into 12 of the amino acid residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 50 residue amino acid polypeptide of IL-6. There is no limit in the claims, as written, that the variance be contiguous. Moreover, there is no limitation stating that the substitution, for example, be a conservative substitution. As a result, there are potentially thousands of variant permutations that could be made. Applicants have not described which portions of the polypeptide are critical to the function of the protein. The specification provides limited guidance regarding which amino acids can be modified in the genus of peptides, while maintaining the desired function. Therefore, these structures (i.e., sequence variants) are claimed only by their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences).
Thus, the genus of claimed peptides is extremely broad because the claims recite generic and incompletely described peptides. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed peptides without adequate descriptions of its component parts or overall makeup. The claims as recited 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 genus of variant peptides recited in the claims.
The invention contemplates peptide variants characterized by having at least 75% sequence identity to a 50 amino acid IL-6 peptide as recited in claim 1 and peptide variants characterized by having at least 90% sequence identity to a 35 amino acid IL-6 peptide as recited in claim 1. The specification does not provide adequate written description to identify the broad and variable genus of peptides because, inter alia, the specification does not disclose a correlation between the necessary structure of the peptide and the function(s) of the peptide; and thus, the specification does not distinguish the claimed genus from others. Accordingly, the specification does not define any structural features commonly possessed by members of the genus of variant peptides. In addition, because the genus of claimed polypeptide is highly variable (i.e., each variant peptide would necessarily have a unique structure; see MPEP 2434), the generic description of the variant peptide is insufficient to describe the genus.
Further, Applicants have not shown possession of a representative number of species of the claimed peptides. As noted above, the claims are generic for the components of the peptide. The disclosure of only a few species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
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.)
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. Bowie et al. (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al. further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three-dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). 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 Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. 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 (page 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 (page 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (page 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (page 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 (page 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 (page 400, paragraph bridging cols 1 and 2).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g., alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e., each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Bowie et al., Lazar et al., Burgess et al., and Greenspan 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 peptides could not be predicted as claimed.
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 peptides in the conjugate. 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 variant proteins 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 peptide such that one would be able to distinguish it from the peptides 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 proteins as claimed.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed IL-6 conjugate. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle& Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). 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).
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).
Therefore, the full breadth of the claims fails to meet the written description provision of 35 U.S.C. §112, first paragraph. In the instant case, for example, Applicants have failed to describe which “variant sequences have at least 75% identity” to a 50 amino acid peptide of IL-6 as claimed. In addition Applicant has failed to describe carrier proteins that are a non-toxic mutant diphtheria toxin, for all the reasons recited above.
Claim Rejections - 35 U.S.C. § 112(b)
5. 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.
5a. Claims 1-7, 11-12 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 pre-AIA the applicant regards as the invention.
Claim 1 is vague and indefinite for several reasons.
Claim 1, lines 4 and 5, is vague and indefinite because it fails to recite that “5 to 50 amino acids” are contiguous.
Similarly, claim 3, line 2 and 3, is vague and indefinite because it fails to recite that “7 to 35 amino acids” are contiguous.
Claim 5, line 2, is vague and indefinite because it fails to recite “at least 5 amino acids” are contiguous.
Claim 1, line 8, is vague and indefinite because it recites “carrier protein is a non-toxic mutant diphtheria toxin” and it is unclear which carrier protein is being claimed.
Claim 1, lines 9-10, is vague and indefinite because it recites “…having at least 75% identity with the sequence of 5 to 50 amino acids of IL-6”, and it is unclear which amino acids sequences in IL-6 are encompassed by the limitation because no amino acid sequence has been recited in the claim. Furthermore, it is unclear which species of IL-6 is encompassed by the claim because IL-6 species are very disparate in amino acid sequence. Human and mouse IL-6 share only about 42% amino acid identity. Additionally, the claim should properly recite “…identity to…”.
Similarly claim 3 is vague and indefinite because it recites “…having at least 90% identity to the sequence of 5 to 50 amino acids of IL-6”,
Claims 1 and 3 rejected as improper because they recite a non-elected invention. It is suggested that the claims be amended to delete recitation of “IL-6R” to obviate this rejection.
Claim 2, line 2, is vague and indefinite because it recites “CRM197”. The full definition of all acronyms should be recited at their first use in a claim.
Claim 3 is rejected as improper because it recites a non-elected invention. It is suggested that the claim be amended to delete recitation of “IL-6R” to obviate this rejection.
Claim 5, line 10, is vague and indefinite because it recites “" RSFKEFLQSSLRALRQM (SEQ ID NO:8 (SEQ ID NO:4), rather than the proper “RSFKEFLQSSLRALRQM (SEQ ID NO:8)”.
Claim 6 is vague and indefinite because recites “via a non-peptide coupling agent” and it is unclear which “non-peptide coupling agents” are encompassed by the claim.
Claim 7 is rejected as vague and indefinite because it recites “the immunogenic conjugate according to claim 1, of the following formula (I): [(AESSKEALAENNLNLPKC)-GMB]-CRM197 (I) in which: the polypeptide consists of the sequence AESSKEALAENNLNLPKC (SEQ ID NO:20)”, however, claim 5 recites “…claim 1 where in the polypeptide comprises at least 5 amino acids of "NKSNMCESSKEALAENNLNLPK (SEQ ID NO:4)” and it is unclear and confusing which polypeptide, SEQ ID NO:4 or SEQ ID NO:20, is present in claim 1 because the amino acid sequences are different.
Furthermore, claim 7, lines 3-6, is vague and indefinite because it recites formula (I): [(AESSKEALAENNLNLPKC)-GMB]-CRM197 (I) in which: the polypeptide consists of the sequence AESSKEALAENNLNLPKC (SEQ ID NO:20)”, however, there is an alanine at the N-terminus, rather than a requisite cysteine residue, to form a cyclized polypeptide with the C-terminal cysteine residue. The specification on page 8, lines 7-24, discloses:
“Cyclization
Preferably, the polypeptide according to the invention is cyclized.
The polypeptide according to the invention can be cyclized, i.e. the entire polypeptide forms a ring or a portion thereof forms a ring, according to methods of
any kind known to the skilled person.
Depending on the functional groups present in the polypeptide, this cyclization can take place in several different ways, such as: from its C-terminal end to its N-terminal end, from its N-terminal end to a side chain, from a side chain to its C-terminal end, or between two side chains. The side chain moieties involved in cyclization notably include -NH2, -COOH and -SH groups.
Among the various modalities of cyclization of polypeptides, can be mentioned the formation of a peptide bond between the two N- and C-terminal ends of the polypeptide, lactamization, lactonization or the formation of a disulfide bond between two cysteines (C) of the polypeptide. In particular, when an inter-cysteine disulfide bond is formed, i.e. between the -SH radicals of two cysteines, the cysteines may already be present in the IL-6 or IL-6R sequence, or they may be added within these sequences, to form variant sequences, or at their N- and/or C-terminus(es).” Therefore, it is unclear how the polypeptide is cyclized.
Regarding claims 11 and 12, the phrase "in particular" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 4 is rejected as vague and indefinite insofar as it depends on the above rejected claim 1 for its limitations.
Claim rejections-35 U.S.C. 103
6. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
6a. Claims 1-6, and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Lucille Desallais et al (2016), in view of WO 2013/021284 A2 and and further in view of WO 2019/228674 Al
The claims of the instant invention are directed to an immunogenic conjugate comprising: - a carrier protein and - at least one polypeptide having at most 100 amino acids comprising a sequence of 5 to 50 amino acids of interleukin 6 (IL-6) or a variant sequence having at least 75% identity with the sequence of 5 to 50 amino acids of IL-6, wherein the polypeptide is covalently linked to the carrier protein and the carrier protein is a non-toxic mutant diphtheria toxin.
Lucille Desallais et al (2016) describes a conjugate comprising a peptide of human interleukin-6 (hIS200), and this peptide corresponds to a region involved in the interaction between interleukin-6 and its receptor IL-6Rα. hIS200 comprises the sequence 78-94 of human interleukin-6: Acetyl + C78ESSKEALAENNLNLPK94CY. This peptide is cyclized by the formation of intramolecular disulfide bridges between the cysteine residues and it is coupled to KLH (Keyhole limpet haemocyanin) via bis(diazo)benzidine (BDB) (See page 2, Methods, first full paragraph). The reference is silent with respect to the non-toxic mutant of diphtheria toxin (CRM197) as carrier protein in the conjugate.
WO 2013/021284 A2 describes a vaccine comprising a peptide derived from interleukin-6 for generating a protective immune response against IL-6, the peptide being conjugated to the carrier protein KLH. (See Example 8, page 10) . The peptides described in the instant application are described in the reference (page 21, Table 2; page 24, Table 3; page 10). The reference (page 10, line 12) also mentions that IL-6 can be bonded to a carrier molecule which can be the diphtheria antitoxin. The reference is silent with respect to CRM197.
WO 2019/228674 Al describes an immunogenic conjugate comprising interleukin-4 or interleukin-13 with a carrier protein being CRM197 or KLH in a pharmaceutical composition with at least one adjuvant, for the treatment of disorders associated with the aberrant expression or activity of IL-4 and/or IL-13 (page 10, lines 6-15; Figure 1, Figure 4, Table 1, Example 1; page 38, lines 1-15). The reference (Figures 4, 5 and 6) compares conjugates having KLH with those comprising CRM197. The conjugates comprising CRM197 are more immunogenic than the conjugates comprising KLH.
Therefore, it would have been obvious to a person skilled in the art at the time of the instant invention to modify the product of Lucille Desallais et al by covalently attaching the IL-6 peptide to a carrier molecule which is diphtheria antitoxin as taught by WO 2013/021284 A2 or with a carrier molecule which is CRM197 as taught by WO 2019/228674 Al, because WO 2019/228674 Al discloses that pharmaceutical compositions comprising immunogenic conjugates comprising CRM197 are more immunogenic than the conjugates comprising KLH. Therefore, a person skilled in the art could be motivated from the teachings of the references to obtain the conjugate comprising the peptide hIS200 described in Lucille Desallais et al bonded to the toxin CRM197 via bis(diazo)benzidine (BDB), which makes it possible to obtain more anti-IL-6 antibodies than with the conjugate of Lucille Desallais which itself comprises KLH as carrier protein. To obtain an immunogenic conjugate inducing a stronger immune response against IL-6 comprising the non-toxic mutant of diphtheria toxin CRM197 as carrier protein and the peptide derived from interleukin-6 bonded by covalent bonding would be obvious to a person skilled in the art at the time of the invention because the non-toxic mutant of diphtheria toxin, CRM197, is well known in the prior art in view of WO 2019/228674 Al which describes immunogenic conjugates comprising interleukin-4 or interleukin-13 bonded to CRM197 (page 56, Table 1; pages 57-58; page 59, table 2; page 60, table 3; Figure 4) and provides the motivation and expectation of success, to obtain an immunogenic conjugate comprising an IL-6 peptide and the non-toxic mutant of diphtheria toxin CRM197 as carrier protein because the reference teaches that conjugates comprising CRM197 are more immunogenic than conjugates comprising KLH.
Therefore, the combination of references renders obvious claims 1-6, and 11-12 in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Claims 1-7, and 11-12 are rejected.
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/PREMA M MERTZ/ Primary Examiner, Art Unit 1646
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