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 .
DETAILED ACTION
Claim Status
Claims 1-5, 9-11, 13-14, 28-29, 31, 37-38, 40-42, 54, 58 are currently pending. Claims 3-5, 9-11, 13-14, 28, 31,37-38, 40-41, 58 have been amended. Claims 6-8, 12, 15-27, 30, 32-36, 39, 43-53, 55-57, 59-63 are canceled. There are no new claims. Claims 1-5, 9-11, 13-14, 28-29, 37 will be examined on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-5, 9-11, 13-14, 28-29, 31, 37) and elected species, VHH-Fc and SEQ ID No: 6 in reply filed on February 11, 2026 is acknowledged. Claims 31, 38, 40-42, 54, 58 are withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to nonelected invention, there being no allowance generic or linking claim. Election was made without traverse in reply filed on February 11, 2026.
Priority
Acknowledgement is made of applicant’s claim for foreign priority based on an application filed on June 11, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement (IDS)
The IDS submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 11, 37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Feng et al. (US 20180319872 A1; hereafter Feng; PTO-892).
As to claims 1-2, Feng teaches “a method of preparing a strain of Saccharomyces yeast engineered to produce one or more of the binding agents defined herein comprising (a) chromosomally integrating a polynucleotide sequence encoding the ABAB binding agent into the genome of the strain of Saccharomyces yeast, and (b) screening the yeast of (a) for production of the binding agent. In certain aspects, the chromosomal integration [0061]. Feng teaches “the method of claim 14, wherein chromosomal integration is performed via: (a) amplifying a polynucleotide sequence encoding the ABAB binding agent from plasmid pCEV-G4-Km-TEF-AT-yABAB hAA6T83N-tagless (SEQ ID NO:90) using primers containing (i) nucleic acid sequence homologous to a selected yeast chromosomal integration site and (ii) nucleic acid sequence homologous to regions 5′ and 3′ of ABAB binding agent coding sequence of the plasmid, to produce an integration cassette, (b) transforming yeast with the integration cassette produced in (a) with pCRI-Sb-δ1 (SEQ ID NO:91) or pCRI-Sb-δ2 (SEQ ID NO:92) to induce a double stranded break within the corresponding yeast chromosomal delta sites under conditions promoting spontaneous integration of the integration cassette into the site of the double stranded break, (c) screening the transformed yeast of (b) for production of the ABAB binding agent”.
Feng also teaches “An engineered strain of Saccharomyces yeast that produces a therapeutic protein having binding specificity for a unique epitope of Clostridium difficile toxin A (TcdA) or toxin B (TcdB), or both” (claim 51). Feng teaches “the engineered strain of Saccharomyces yeast of claim 51, wherein the Saccharomyces strain is S. cerevisiae or S. boulardii” (claim 52). Feng teaches “the engineered strain of Saccharomyces yeast of claim 51 or 52, wherein the therapeutic protein is an antibody” (claim 53). Feng also teaches, the engineered strain of Saccharomyces yeast of claim 51 or 52, wherein the strain of Saccharomyces yeast is engineered by (a) chromosomally integrating a polynucleotide sequence encoding the therapeutic protein into the genome of the strain of Saccharomyces yeast, and (b) screening the yeast of (a) for production of the therapeutic protein” (claim 55).
As to claim 3, Feng teaches “Two modifications to a wild-type S. boulardii strain can be made to preserve the in vivo stability of the expression plasmid conferred by the yeast URA3 metabolic selection marker: 1) a diploid auxotrophic mutant carrying a deletion in both chromosomal alleles of URA3 can be constructed, and 2) the endogenous 2 micron circle can be cured from S. boulardii to prevent unintended recombination from interfering with ABAB expression” [0265]. Feng also teaches that “the most straightforward and efficient method for constructing auxotrophic mutants in wild-type Saccharomyces strains involves targeted deletion of chromosomally encoded genes by homologous recombination, which occurs at very high frequencies in Saccharomyces. Complete deletion of the targeted gene is preferred over selection of spontaneous mutations which can revert back to the wild type. Thus, a gene deletion is preferred for the haploid state in S. cerevisiae which is typically induced from wild-type diploid via sporulation using a nutritionally poor growth medium and incubating at low temperature (30° C.). However, S. boulardii is sporulation deficient and recalcitrant to formation of haploid cells under normal sporulation conditions [64,65]. A two-step process for deletion of both chromosomal gene alleles (e.g. URA3) was used in which each deletion step can be selected for. The process is outlined schematically in FIG. 16. (see Figure 16)” [0266].
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As to claim 11, Feng teaches “Antibody-based binding agents derived from human and camelid immunoglobulins, as well as strains of yeast engineered to secrete the binding agents, and methods of treating and preventing Clostridium difficile infections using the engineered strains of yeast. These binding agents recognize and bind with specificity to Clostridium difficile toxin A and/or toxin B and in some cases exhibit toxin neutralizing activity. The binding agents include camelid V.sub.HH peptide monomers, linked groups of V.sub.HH peptide monomers, V.sub.HH peptide monomers joined to antibody Fc domains, and V.sub.HH peptide monomers joined to IgG antibodies”. Feng also teaches “the present invention is directed to binding agents comprising V.sub.HH peptide monomers and linked groups of V.sub.HH peptide monomers comprising two, three, four, or more monomers, each of which binds TcdA and/or TcdB, preferably with specificity. Thus, the invention encompasses V.sub.HH peptide binding agents comprising at least one V.sub.HH peptide monomer, wherein each V.sub.HH peptide monomer has binding specificity for an epitope of C. difficile toxin A (TcdA) or toxin B (TcdB). In certain aspects, these binding agents comprise two, three, four, or more linked V.sub.HH peptide monomers. The V.sub.HH peptide monomers include, but are not limited to, the V.sub.HH peptide monomers 5D (SEQ ID NO:1), E3 (SEQ ID NO:3), AA6 (SEQ ID NO:5), and AH3 (SEQ ID NO:7) [011]. “In aspects of this embodiment where two or more monomer are linked, the monomers may be linked by flexible peptide linkers, generally comprising between 10 and 20 amino acids. Suitable linkers include, but are not limited to, linker-1 (SEQ ID NO:9), linker-2 (SEQ ID NO:11), and linker-3 (SEQ ID NO:13)” [0012].
As claim 37, Feng teaches “an engineered strain of Saccharomyces yeast that produces a V.sub.HH peptide binding agent comprising at least one V.sub.HH peptide monomer, wherein each V.sub.HH peptide monomer independently has binding specificity for a unique epitope of Clostridium difficile toxin A (TcdA) or toxin B (TcdB)” (claim 31). “The engineered strain of Saccharomyces yeast of claim 34, wherein two of the V.sub.HH peptide monomers have binding specificity for epitopes of TcdA and two of the V.sub.HH peptide monomers have binding specificity for epitopes of TcdB” (claim 35).
Feng also teaches “the engineered strain of yeast of claim 1, wherein the binding agent is ABAB, wherein the first and third monomers have binding specificity for epitopes of TcdA and the first and third monomers are V.sub.HH peptide monomers AH3 (SEQ ID NO:7) and AA6 (SEQ ID NO:5), respectively, and wherein the second and forth monomers have binding specificity for epitopes of TcdB and the second and forth monomers are V.sub.HH peptide monomers 5D (SEQ ID NO:1) and E3 (SEQ ID NO:3), respectively” (claim 5). See for example Figure 21.
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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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Claims 4-5, 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Feng et al. (US 20180319872 A1; hereafter Feng; PTO-892) in view of Siewers et al. (Published in 2014; hereafter Siewers; PTO-892) as applied to claims 1-3, 11, 37 above.
Feng teaches the limitations of claims 1-3, 11, 37 as fully discussed above and incorporated herein.
However, Feng does not teach an engineered Saccharomyces yeast strain comprising complete or partial deletion of GAP1, or wherein the yeast is ura3 (-/-) and gap1 (-/-), or wherein a yeast strain comprising a nucleic acid sequence encoding dihydrofolate reductase (DHFR) incorporated into the yeast’s genome.
Siewers teaches numerous selection marker genes that have been employed for genetic manipulation of Saccharomyces strains, including URA3, GAP1 and E. coli DHRF, which is pertinent to claims 4-5, 9-10. See for example page 5-10, Table 1-5.
It would be obvious to one of skill in the art to combine the teachings of Feng and Siewers, thereby arriving at the invention of claims 4-5, 9-10. Since the URA3 deletions in the genome of Saccharomyces strains of Feng were shown to be effective to select the desired engineered yeast strains, it would have been obvious to substitute these known equivalents; MPEP 2144.06.
Claims 14, 28 are rejected under 35 U.S.C. 103 as being unpatentable over Feng et al. (US 20180319872 A1; hereafter Feng; PTO-892) in view of Siewers et al. (2014; hereafter Siewers; PTO-892), as applied to claims 1-3, 11, 37 above and further view of Crowe et al. (US 20190307891 A1; hereafter Crowe; PTO-892).
Feng teaches the limitations of claims 1-3, 11, 37 as fully discussed above and incorporated herein.
However, Feng does not teach therapeutic polypeptide is a cytokine or wherein the therapeutic polypeptide binds to TNF alfa.
Crowe teaches a bispecific antibody comprising at least one anti-TNF-alpha antibody or antigen-binding fragment thereof and at least one anti-IL-6 antibody or antigen-binding fragment thereof [0008]. Crowe also teaches that TNF-alfa is a cytokine, compositions and constructs comprising a TNF-alpha binding polypeptide and an IL-6R binding polypeptide. Crowe teaches the treatment with an anti-TNF-alpha binding polypeptide and an anti-IL-6R binding polypeptide together was surprisingly more effective than treatment with each binding polypeptide alone. See for example [0645].
Crowe teaches nucleic acids encoding such constructs, to methods for preparing such compositions and constructs, to cDNA and vectors comprising nucleic acids encoding such constructs, to host cells expressing or capable of expressing such constructs and to uses of such compositions and constructs. See for example [0002], [0003]. Crowe teaches that TNF-alpha binding polypeptide and the IL-6R binding polypeptide comprised in the composition of the invention are linked to each other (thereby forming a single construct). Such a format may be convenient for recombinant expression purposes. See for example [0037].
Crowe teaches DNA integrated into S. cerevisiae’s genome via transformation carried out with a linearized MCI vector. See for example [054]. Crowe teaches that immunoglobulin chain variable domains such as VHNVHHs can be produced using S. cerevisiae. See for example [0536].
It would be obvious to one of skill in the art to combine the teachings of Feng and Crowe, thereby arriving at the invention of claims 14, 28. Since the production of anti-TNF alfa and IL-6, and immunoglobulin chain variable domains in the yeast, Saccharomyces was taught by Crowe and the site-specific genomic integrations of VHH-Fc sequences of Feng were shown to be effective in producing therapeutic polypeptides, it would have been obvious to substitute these known equivalents; MPEP 2144.06.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Feng et al. (US 20180319872 A1; hereafter Feng; PTO-892) in view of Siewers et al. (2014; hereafter Siewers; PTO-892) as applied to claims 1-3, 11, 37 above, and further in view of Crowe et al. (US 20190307891 A1; hereafter Crowe; PTO-892) as evidenced by Liu et al. (Published on October 6, 2020; hereafter Liu; PTO-892).
Feng teaches the limitations of claims 1-3, 11, 37 as fully discussed above and incorporated herein.
However, Feng does not teach wherein the cytokine is IL-22 or IL-10.
Liu teaches a robust method to integrate recombinant genes into the Ty elements of Saccharomyces boulardii. Liu also teaches stable S. boulardii cell lines that secreted various anti-inflammatory proteins, including IL-10.
It would be obvious to one of skill in the art to modify the teachings of Feng by selecting the site-specific genomic integrations of antibody-based binding agents derived from human and camelid immunoglobulins in Saccharomyces strains, there by arriving at the invention of claim 29. Since the antibody-based binding agents of Feng and the IL-10 gene stable inserted into the Saccharomyces boulardii of Liu and were shown to be effective for producing therapeutic proteins, it would have been obvious to substitute these known equivalents; MPEP 2144.06.
See MPEP 2144(II): “The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art … that some advantage or expected beneficial result would have been produced by their combination.
Reasonable expectation of success would be expected because Feng specifically teaches engineered probiotic Saccharomyces strain comprising site-specific chromosomal insertion of DNA sequences encoding antibody-based fusion protein binding agents that bind C. difficile antigens TcdA and TcdB and does not specify any other antibody-based fusion protein binding agents that should not be site-specific inserted into the Saccharomyces strain’s genome.
Also, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain predictable results is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results". In the instant case, Feng teaches a product (and method) that only differs from the claimed invention by the substitution of a single component (i.e. substitution of a therapeutic polypeptide); the substituted element (i.e. IL-10) was already known and known to function as a therapeutic polypeptide, therefore no change in the function of the substituted element occurred; and one of ordinary skill in the art would be capable of choosing a therapeutic polypeptide sequence, such as IL-10 disclosed as being useful with a reasonable expectation of success (i.e. the substitution of the element would lead to predictable results), particularly because Feng teaches site-specific insertion of antibody-based fusion protein binding agents sequences into Saccharomyces’ chromosome. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Conclusion
Claim 13 is allowable.
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Feng teaches an engineered strain of Saccharomyces yeast comprising at least one site-specific chromosomal insertion of a nucleic acid encoding therapeutic polypeptide having binding specificity for a unique epitope of Clostridium difficile toxin A (TcdA) or toxin B (TcdB), or both.
Crowe teaches TNF-alpha binding polypeptide and the IL-6R binding polypeptide integrated into the genome of a Saccharomyces strain.
Liu teaches a robust method to integrate recombinant genes into the Ty elements of Saccharomyces boulardii. Liu also teaches stable Saccharomyces boulardii cell lines that secreted various anti-inflammatory proteins, including IL-10, TNFR1-ECD, alkaline phosphatase, and atrial natriuretic peptide (ANP), were successfully created and investigated for their efficacies to the DSS-induced colitis in mice through oral administration.
However, the engineered strain of Saccharomyces comprising the SEQ ID NO: 6, which is a TNF-alfa antibody sequence encoded by a nucleic acid sequence inserted into the yeast’s genome as disclaimed in the present invention is an innovative step because there is no records or indication of a yeast encoding the SEQ ID NO: 6 in any of the arts searched for the purpose of this examination.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PRICILA HAUK TEODORO whose telephone number is (571) 272-2784. The examiner can normally be reached M-F 6:15AM-3:00PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached at (571) 272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PRICILA NMN HAUK TEODORO/Examiner, Art Unit 1645
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
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