Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
1. Applicant’s response filed on September 22, 2025 is acknowledged. With this amendment the issue of non-compliance has been clarified. Said amendment notes that this listing of claims replaces all prior versions and listing of claims in the application. With this amendment original claims 1-12 are canceled and claims 13-22 are added. Claims 13-22 are currently pending and under examination.
Information Disclosure Statement
2. The information disclosure statement (IDS) submitted on February 20, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. An initialed copy is attached hereto.
Claim Objections
3. Claim 13 is objected to because of the following informalities: on first sight, ‘E. coli’ should recite ‘Escherichia coli’. Appropriate correction is required.
4. Claim 19 is objected to because of the following informalities: Said claim recites in part, ‘….bacterium a is pathogenic’ it should be ‘….bacterium is a pathogenic’. Appropriate correction is required.
Claim Rejections - 35 USC § 112
Written Description Rejection
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.
5. Claims 13-22 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.
Independent claim 13 is drawn to an E. coli expression system for producing a bioconjugate vaccine against at least one bacterium comprising: a nucleotide sequence encoding an oligosaccharyltrasferase (OST/OTase) which is PglB; a nucleotide sequence encoding a protein carrier which is genetically detoxified Exotoxin of Pseudomonas aeruginosa (EPA) comprising at least two inserted consensus sequences, D/E-X-N-Z-S/T, wherein X and Z may be any natural amino acid except proline and a targeting polypeptide sequence; and at least one antigenic polysaccharide synthesis gene cluster from at least one bacterium, wherein the antigenic polysaccharide synthesis gene cluster encodes a bacterial O-antigen from one or more strains of Shigella, Escherichia coli (E. coli), Pseudomonas aeruginosa and Francisella tularensis.
Independent claim 21 is drawn to an E. coli expression system for producing a Shigella bioconjugate vaccine comprising: a protein carrier comprising
a nucleotide sequence encoding a genetically detoxified Exotoxin of Pseudomonas aeruginosa (EPA) that has been modified to contain at least two consensus sequences D/E-X-N-Z-S/T, wherein X and Z is any natural amino acid except proline; and
a nucleotide sequence encoding at least one polysaccharide chain linked to an asparagine residue of the D/E-X-N-Z-S/T consensus sequence of the protein carrier and having the following structure:
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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.”
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus of bacterial infections to be vaccinated against as well as the particular components of said vaccine composition capable of the claimed functionality or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession of the claimed invention. In the instant case, to fulfill the written description requirement, a representative number of bacterial infections and components within the bioconjugate vaccine need to be described.
A representative number of species means that the species that are adequately described are representative of the entire genus. 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 Applicant was in possession of the claimed genus.
The claims are broadly drafted in that it comprises an expression system comprising any nucleotide sequence that encodes PglB. This includes subsequent sequences which have at least 90% sequence identity. As well as any nucleotide sequence encoding a protein carrier comprising at least two inserted consensus sequences; and any antigenic polysaccharide syntheses gene cluster all having the distinct ability to act as a vaccine to provide prophylaxis against any bacterium.
While, the specification notes that bioconjugate vaccines can be used to treat or prevent bacterial diseases, such as diarrhea, nosocomial infections and meningitis; and may have therapeutic and/or prophylactic potential for cancer or other diseases. Further, paragraph 0127, notes that conjugate vaccines can be administered to children to protect against bacterial infections and can provide a long lasting immune response to adults. Constructs of the invention have been found to generate an IgG response in animals. It has been found that an IgG response to a Shigella O-specific polysaccharide-protein conjugate vaccine in humans correlates with immune protection in humans.
Further, synthesized complexes of polysaccharides (i.e., sugar residues) and proteins (i.e., protein carriers) can be used as conjugate vaccines to protect against a number of bacterial infections (paragraph 0129). Gram-negative bacteria additionally have an outer membrane over the cell membrane, with a periplasmic space separating the two membranes. In addition, they contain lipopolysaccharides at the surface. When Gram-negative bacteria, such as E. coli, is used to produce a conjugate vaccine of the present invention, the glycoprotein used in the conjugate vaccine is assembled in the periplasmic space.
The disclosure continues with conjugate vaccines having been successfully used to protect against bacterial infections. The conjugation of an antigenic polysaccharide to a protein carrier is required for protective memory response, as polysaccharides are T-cell independent antigens. Polysaccharides have been conjugated to protein carriers by different chemical methods, using activation reactive groups in the polysaccharide as well as the protein carrier (see paragraph 0133). However, the specification really only specifically describes that the lipid-linked oligosaccharide then flip-flops (diffuses transversely) into the periplasmic space by a flipppase, e.g., PgIK. In the final step of N-linked protein glycosylation, the oligosaccharyltransferase (e.g., PglB) catalyzes the transfer of the oligosaccharide from the carrier lipid to Asn residues within the consensus sequence Asp/Glu-Xaa-Asn-Zaa-Ser/Thr (i.e., D/E-X N-Z-S/T), where the Xaa and Zaa can be any amino acid except Pro (FIG. 7A). They have successfully transferred the glycosylation cluster for the heptasaccharide into E. coli and were able to produce N-linked glycoproteins of Campylobacter (see paragraph 0137).
The enzyme will also transfer a diverse array of undecaprenyl pyrophosphate (UPP) linked oligosaccharides if they contain an N-acetylated hexosamine at the reducing terminus. The nucleotide sequence for pglB is provided at SEQ. ID NO. 1, whereas the amino acid sequence for PglB is provided at SEQ. ID. NO. 2. (see paragraph 0138). Separately, a carrier protein depicted as a spiral and containing consensus sequence D/E-X-N-Z-S/T (i.e., Asp/Glu-Xaa-Asn-Zaa-Ser/Thr) is translated in the cytoplasm and is secreted into the periplasmic space. In the final step, an oligosaccharyl transferase (OST or OTase) (e.g., PglB) transfers the heptasaccharide to Asn residues within a consensus sequence of the carrier protein to produce a glycoprotein (see paragraph 0139). In an embodiment of the expression system for a bacterial bioconjugate, DNA encoding the inducible oligosaccharyltransferase and carrier protein can be stably integrated into a bacterial (e.g., E. coli) genome such that genes for antibiotic selection can be omitted. For example, as shown in FIG. 5B, PglB and EPA is integrated into genomic DNA, whereas plasmid DNA, which is interchangeable (i.e., exchangeable), encodes a polysaccharide synthesis gene cluster.
In another embodiment, FIG. 8B shows an expression system for a bacterial bioconjugate that includes three plasmids. A first plasmid codes for the carrier protein, e.g., AcrA from Campylobacter jejuni, which has two N-glycosylation sites and is directed to the periplasm by a PeIB signal peptide. A second plasmid codes for the OST/OTase, e.g., PglB from C. jejuni, which is membrane-bound. A third plasmid is a native plasmid that codes, e.g., for a polysaccharide (O antigen) synthesis cluster, such as that for Shigella dysenteriae 01 (see paragraph 0143).
Beyond this teaching, the specification does not support or fully describe the breadth of the invention, nor has it provided an adequate written description for the method as claimed. Furthermore, the specification does not provide adequate support for the invention as claimed as there are no specific examples of the broadly claimed composition capable of functioning in the manner the claims require. As it pertains to any claims that recite ‘vaccine’, the office takes the position, unless or until clarified that it encompasses the prevention of bacterial conditions, to be a prophylactic composition, once administered it must induce a protective immune response demonstrated by challenge experiments in an acceptable animal model. The specification does not provide substantive evidence that consumption of the expression system comprising a bioconjugate vaccine, as claimed, is capable of preventing against any or all bacteria. This demonstration is required for the skilled artisan to be able to use the claimed composition for their intended potential purpose of prevention. Without this demonstration, the skilled artisan would not be able to reasonably predict the outcome of the administration of the claimed composition, i.e. would not be able to accurately predict if protective immunity has been induced.
Additionally, the instant claims are drawn to an expression system comprising OST/OSTase, protein carriers and EPA comprising “at least about” 90% sequence identity. These proteins are required to perform specific functions, including contributing to a broad group of genera of disorders, which do not necessarily have shared symptoms, pathology, or etiology.
With the exception of SEQ ID NO: 1, 2, 6, and 7, the skilled artisan cannot envision the detailed chemical structure of the encompassed proteins, 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.
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 USPQ2datl966.
Protein chemistry is 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 (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 Bowie et al., Lazar 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 could not be predicted based on sequence identity. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner. Therefore, only SEQ ID NO: 2, 6 and 7, but not the full breadth of the claims, meet the written description provision of 35 USC 112, first paragraph.
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. The Guidelines for Examination of Patent Applications under the 35 USC §112 paragraph 1, “Revision 1” of Written Description Requirement (66 FR 1099-1111, March 25, 2008) state, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the Applicant was in possession of the claimed invention (ld. At 1104). 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. Absent a detailed and particular description of a representative number, or at least a substantial number of the genus of the stated variables and bacterial conditions as related to the claimed bioconjugate composition, the skilled artisan could not immediately recognize or distinguish members of the claimed genus. Therefore, because the art is unpredictable, in accordance with the Guidelines, the description of a particular derivative is not deemed representative of the genus of immunogenic compositions to which the claims refer and hence do not meet the written description requirements.
Conclusion
6. No claim is allowed.
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAKIA J JACKSON-TONGUE whose telephone number is (571)272-2921. The examiner can normally be reached Monday-Friday 930AM-530PM.
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/LAKIA J JACKSON-TONGUE/Examiner, Art Unit 1645 December 18, 2025
/BRIAN GANGLE/Primary Examiner, Art Unit 1645