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
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 .
Applicant’s submission filed on June 16, 2026 has been entered and considered. Rejections and/or objections not reiterated from the previous action mailed February 17, 2026 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
Applicant's election with traverse of Group 1, claims 1-13 and the species of SEQ ID NO: 13 which corresponds to claims 1, 3-6, and 9-13 in the reply filed on December 25, 2025 is acknowledged. The traversal is on the ground(s) that the common technical feature shared by all groups is a polynucleotide encoding an antibody-related molecule and a polynucleotide encoding a modified signal peptide having a specific 6-mer of amino acid residues at the C-terminus which has the same function of extracellularly secreting the antibody related molecule in all groups (Pg. 8 of Remarks). Applicant asserts that the claims of Groups 2 and 3 drawn to the Bacillus host cell and method of producing an antibody related molecule comprising culture of the Bacillus host cell depend on the limitations of claim 1 (Pg. 10). Applicant further traverses that the species of C-terminal amino acid residues in the modified signal peptide do share a common core structure (see table on Pg. 10).
In view of the prior art and Applicant’s traversal related to Groups 2 and 3, Group 2, claim 14 and Group 3, claim 15 have been rejoined. Additionally, all species have been rejoined, which encompass claims 1-13.
Claim 1 has been amended to specify that the positions of X1-X6 in the C terminus and to clarify first and second polynucleotides. Claim 1 has also been amended to incorporate the limitations of claim 10 related to the antibody related molecule being a VHH, the limitations of claim 6 reciting the N-terminal regions, and a limitation reciting expression and extracellular secretion from a Bacillus bacterium. Claims 5-6, 9-10, and 16 have been canceled. Claims 8 and 17 were previously canceled. Claims 18 and 19 have been newly added.
Claims 1-4, 7, 11-15, and 18-19 are pending and examined on the merits.
New Claim Rejections - 35 USC § 112(a) - Written Description
This is a new rejection necessitated by Applicant’s amendment. However, this rejection shares substantial similarity to the rejection as previously set forth in the office action dated February 17, 2026.
The following new rejection provides additional interpretation of the claims which is necessitated by Applicant’s amendment. Any aspect of Applicant’s traversal that pertains to the rejection as newly set forth will be provided following the new statement of rejection.
Claims 1-4, 7, 11-15, and 18-19 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 1 encompasses a nucleic acid construct for the expression and extracellular secretion of a genus of antibody-related molecules which are a variable domain of a heavy chain of heavy chain antibody (VHH) from a genus of Bacillus bacteria comprising a genus of first polynucleotides encoding the antibody-related molecules and a genus of second polynucleotides encoding a modified signal peptide comprising the amino acid residues of X1X2X3X4X5X6 at the final 6 positions of the C terminus where X1 is G, P, or A; X2 is G; X3 is P, S, or A and X1X2X3 are not GGP; X4 is A; X5 is S, H, or F; and X6 is A and wherein a region of the N-terminus to position 7 of the modified signal peptide consists of a genus of amino acid sequences of SEQ ID NO: 10 or 11 or an amino acid sequence having at least 90% identity thereto, while the specification only discloses a fixed number of species of 6-mers of amino acids at the C-terminus of the modified signal peptide, a fixed number of species of the N-terminal sequences having 90% or greater identity to SEQ ID NOs: 10 or 11, and a fixed number of Bacillus strains.
In regard to the scope of modified signal peptides, Applicant’s specification describes the genus of modified signal peptides as being produced by modification of the C-terminal region of parent signal peptides (Para. [0029]), comprising the amino acid residues of X1X2X3X4X5X6 at the final 6 positions of the C terminus where X1 is G, P, or A; X2 is G; X3 is P, S, or A and X1X2X3 are not GGP; X4 is A; X5 is S, H, or F; and X6 is A (Para. [0031]), and comprising a region from the N-terminus to position 7 as counted from the C-terminus which consists of the amino acid sequence of a signal peptide of Bacillus bacteria other than the C-terminal region or an amino acid sequence having at least 90% sequence identity to a signal peptide of Bacillus bacteria which preferred embodiments of SEQ ID NO: 10 or 11 or an amino acid sequence having at least 90% sequence identity thereto (Para. [0032]). Additionally, Applicant’s specification also describes modifications to the N-terminal region which may consist of amino acid sequences having deletions, substitutions, additions, or insertions of one or several amino acid residues (Para. [0032]).
In regard to the scope of the host cell, Applicant’s specification describes a genus of Bacillus bacteria and provides examples of Bacillus subtilis, Bacillus cereus, Bacillus thuringiensis, Bacillus megaterium, Bacillus amyloliquefaciens, Bacillus pumilus, and Bacillus liqueniformis (interpreted as B. licheniformis), and mutant strains thereof (Para. [0024]).
Dependent claim 2 encompasses a genus of polynucleotides encoding a modified signal peptide comprising the amino acid residues of X1X2X3X4X5X6 at the final 6 positions of the C terminus where X1 is G, P, or A; X2 is G; X3 is P or S; X4 is A; X5 is S or H; and X6 is A.
Dependent claims 3-4 encompass a genus of polynucleotides encoding a modified signal peptide comprising the amino acid residues having SEQ ID NOs: 13-30.
Dependent claim 7 encompasses a genus of modified signal peptides consisting of an amino acid sequence of SEQ ID NOs: 31-35, (i.e. an N-terminal region of SEQ ID NO: 10 and C-terminus of SEQ ID NOs: 25-28 or N-terminal region of SEQ ID NO: 11 and C-terminus of SEQ ID NO: 15).
Dependent claims 11-12 encompasses a genus of promoters operably linked to the antibody-related molecules.
Dependent claim 13 encompasses a genus of expression vectors comprising the nucleic acid construct of claim 1.
Dependent claim 14 encompasses a genus of recombinant Bacillus bacteria comprising the nucleic acid construct of claim 1.
Dependent claim 15 encompasses a genus of methods of producing an antibody-related molecule comprising culturing the Bacillus of claim 14 and collecting the extracellularly secreted antibody-related molecule. In regard to the scope of antibody-related molecule, Applicant’s specification describes the genus of antibody-related molecules to include an immunoglobulin or a single domain or combination of two or more domains selected from the domains constituting an immunoglobulin and provides examples of domains of immunoglobulin heavy chain, i.e. VH, CH1, CH1, and CH3, and domains of immunoglobulin light chain, i.e., VL and CL. Applicant further provides exemplary embodiments of IgG, Fab, F(ab’)2, ScFv, a diabody, and a VHH (Para. [0007]).
Dependent claim 18 encompasses a genus of nucleic acid constructs of claim 1 wherein the N-terminal region consists of an amino acid sequence of SEQ ID NO: 11 or an amino acid sequence having 90% identity thereto and wherein X1-X6 consists of the amino acid sequence of SEQ ID NOs: 13-30.
Dependent claim 19 encompasses a genus of nucleic acid constructs of claim 1 wherein the N-terminal region consists of an amino acid sequence of SEQ ID NO: 10 or an amino acid sequence having 90% identity thereto and wherein X1-X6 consists of the amino acid sequence of SEQ ID NOs: 13, 15-18, or 23.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) 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 written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
ACTUAL REDUCTION TO PRACTICE
In regard to independent claims 1 and dependent claims 2-4 encompassing a nucleic acid construct for the expression and extracellular secretion of a VHH from a Bacillus bacteria comprising a genus of first polynucleotides encoding a VHH and a genus of second polynucleotides encoding a modified signal peptide comprising the amino acid residues of X1X2X3X4X5X6 at the final 6 positions of the C terminus and an N-terminus of the modified signal peptide consisting of a genus of amino acid sequences of SEQ ID NO: 10 or 11 or an amino acid sequence having at least 90% identity thereto, Applicant discloses a limited number of modified signal peptides comprising specific amino acid residues (SEQ ID NO: 13-30, 82-84; see Tables 3 and 4) which are linked with N terminal regions having 100% sequence identity to SEQ ID NO: 10 (yncM) or SEQ ID NO: 11 (S237) for expression of two VHHs, 1ZVY and 5IMM, in a single Bacillus subtilis Dpr9 ΔsigF strain (See Table 3). It is noted that while Applicant has disclosed signal peptide combinations of the N-terminal region of SEQ ID NO: 11 with C-terminus regions of SEQ ID NOs: 13-30 and 82-84, Applicant has only disclosed signal peptide combinations of N-terminal region of SEQ ID NO: 10 with C-terminus regions of SEQ ID NO: 13, 15-18 and 23 (Tables 3-5).
In regard to dependent claim 7 encompassing a genus of modified signal peptides consisting of an amino acid sequence of SEQ ID NOs: 31-35, (i.e. an N-terminal region of SEQ ID NO: 10 and C-terminus of SEQ ID NOs: 25-28 or N-terminal region of SEQ ID NO: 11 and C-terminus of SEQ ID NO: 15) which can be used for expression and extracellular secretion of a VHH in a Bacillus bacterium, Applicant has disclosed extracellular secretion of VHH in B. subtilis.
In regard to dependent claims 11- 13 encompassing a genus of vectors and promoters comprising the nucleic acid construct of claim 1, as stated above Applicant discloses a limited number of nucleic acid constructs of claim 1.
In regard to dependent claims 14-15 encompassing a genus of host cells which are Bacillus bacteria comprising the nucleic acid construct of claim 1 and a method of producing an antibody-related molecule comprising culturing the Bacillus of claim 14, as stated above, Applicant discloses a limited number of antibody related molecules (i.e., VHHs 1ZVY and 5IMM, Table 3), a limited number of nucleic acid constructs of claim 1 and also a limited number of Bacillus host cells, specifically a Bacillus subtilis Dpr9 ΔsigF strain.
In regard to dependent claim 18, encompassing a genus of a nucleic acid constructs of claim 1 wherein the N-terminal region consists of an amino acid sequence of SEQ ID NO: 11 or an amino acid sequence having 90% identity thereto and wherein X1-X6 consists of the amino acid sequence of an of SEQ ID NOs: 13-30, as stated above, Applicant discloses N terminal regions having 100% sequence identity to SEQ ID NO: 11.
In regard to dependent claim 19, encompassing a genus of a nucleic acid constructs of claim 1 wherein the N-terminal region consists of an amino acid sequence of SEQ ID NO: 10 or an amino acid sequence having 90% identity thereto and wherein X1-X6 consists of the amino acid sequence of an of SEQ ID NOs: 13, 15-18, or 23, as stated above, Applicant discloses N terminal regions having 100% sequence identity to SEQ ID NO: 10.
However, as stated above, Applicant was only in possession of a limited number of nucleic acid constructs comprising C-terminal SEQ ID NOs which can be used in combination with a limited number of N-terminal SEQ ID NOs for expression and extracellular secretion of a limited number of VHHs in a single strain of Bacillus subtilis.
DISCLOSURE OF STRUCTURE
Applicant has provided sequence listings of SEQ ID NOs of the C-terminus of the modified signal peptides (SEQ ID NO: 13-30), sequence listings of SEQ ID NOs of the N-terminus of the modified signal peptides (SEQ ID NOs: 10 and 11), two embodiments of an antibody-related molecule which is a VHH (1ZVY and 5IMM), and a single embodiment of host cell, Bacillus subtilis Dpr9 ΔsigF. Although use of signal peptides for secretion of heterologous proteins in host cells such as Bacillus are known, the art indicates that choosing a signal peptide having functional ability is unpredictable and depends on the signal peptide, the heterologous protein, and the specific host cell and current programs which can be used to select effective signal peptides are unreliable (see more below). Neither the specification nor the art indicate a relationship between the structure of the instantly claimed genus of modified signal peptides and the ability to function in a nucleic acid construct for the expression and extracellular secretion of an antibody-related molecule in any host Bacillus.
SUFFICIENT RELEVENT IDENTIFYING CHARACTERISTICS
As stated above, the embodiments of specific C-terminal amino acid SEQ ID NOs (SEQ ID NOs: 13-30) which are able to be linked to specific N-terminal amino acid SEQ ID NOs (S237/SEQ ID : 11 or yncM/SEQ ID NO:10) in order to generate modified signal peptides which can be used for expression and extracellular secretion of specific VHHs (1ZVY or 5IMM) in a Bacillus subtilis Dpr9 ΔsigF strain are provided (see Tables 3-5).
Accordingly, if a skilled artisan sought to generate the claimed genus of nucleic acid constructs for expression and extracellular secretion of a VHH, they would need to know which specific 6-mer amino acid sequence of the C-terminus could be linked to which specific amino acid sequence of the N-terminus and be able to predictably produce a construct which can be used for the expression and extracellular secretion of any VHH in any Bacillus host cell.
The breadth of the claims encompass a genus of C-terminal and N-terminal amino acid sequences which can be linked in various combinations and used as a signal peptide for expression and extracellular secretion of any VHH in any Bacillus. Although Applicant has disclosed sequences for 18 modified C-terminal regions, there are six amino acid sequences encompassed by claim 1 (PGPASA, PGPAHA, PGPAFA, AGAASA, AGAAHA, AGAAFA) and two amino acid sequences encompassed by claim 2 (PGPASA, PGPAHA) which have not been reduced to practice. Similarly, regarding the N-terminal region, the breadth of the claims encompass amino acids sequences having 90% homology to SEQ ID NOs: 10 and 11. SEQ ID NO: 10 consists of 34 amino acids and SEQ ID NO: 11 consists of 23 amino acids. Therefore, the claims encompass amino acid sequences of SEQ ID NO: 10 in which approximately three amino acids have been altered and SEQ ID NO:11 in which approximately two amino acids have been altered. However, the specification provides no guidance nor description as to any rationale in choosing the amino acid sequences that were identified or where amino acid sequences could be modified, therefore the skilled artisan would not know what approach to take to select C-terminus amino acid sequences, modify the N-terminus sequence, or choose combinations of N-terminal and C-terminus amino acid sequences which could be used as a signal peptide with any predictable outcome on expression and extracellular secretion of any VHH in any Bacillus host.
Therefore, it is incumbent on the applicant to provide this nexus between structure and function in order to be given credit for possession of a larger genus of polynucleotides comprising amino acid sequences used as a modified signal peptide for expression and extracellular secretion of a VHH in Bacillus beyond those comprising the individual disclosed species. Otherwise, the Written Description guidelines suggest that the Applicant is entitled to only the species specifically recited as having this activity. Moreover, even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART AND QUANTITY OF EXPERIMENTATION
The nucleic acid construct comprising signal peptides which can be used for expression and extracellular secretion of a VHH of the claimed invention is not well established. Although the use and screening of signal peptides for expression and extracellular secretion of a protein is routine and conventional, one of ordinary skill in the art would neither expect nor predict the claimed functioning of the modified signal peptide according to the genus of nucleic acid constructs comprising a modified signal peptide for the expression and secretion of a VHH as broadly as is instantly claimed as the art indicates there is a high degree of unpredictability in choosing signal peptides for heterologous protein expression in various host cells.
Brockmeier et al. (found in IDS dated 04/25/2025) teaches that the most effective signal peptide for use in secretion of one protein is not necessarily the most effective or even a sufficient signal peptide for secretion of a different target protein in B. subtilis and that signal peptides must be optimized based on the individual protein of interest which is to be secreted (Abstract; Fig 5; Pg. 399, left col. 2nd para.). Additionally, Brockmeier et al. teaches that known programs which purport to predict optimal signal peptides for heterologous protein secretion are unreliable (Table 1, Pg. 399, left col., 3rd para.). Further, Brockmeier et al. teaches that the N-terminal region of the protein also plays a role in the secretion efficiency and that optimal interaction between signal peptide and target protein for secretion is critical (Pg. 399, left col., 1st para.). Brockmeier et al. ultimately concludes that secretion efficiency for a protein in B. subtilis is determined by “a complex pattern of events.” (Pg. 399, right col. 3rd para.).
Freudl et al. (2018, Signal peptides for recombinant protein secretion in bacterial expression systems. Microbial Cell Factories, 17(1), 52) teaches that modifications to signal peptides in the N-terminal region which result in alterations of the net charge of the N-terminal region can either increase or decrease secretion efficiency based on the signal peptide being modified and target protein being secreted (Pg. 6, right col., last para. and Pg. 7, left col. 1st para.). Similarly, Freudl et al. teaches that amino acid alterations in the central H-region can also influence effectiveness of a signal peptide with effectiveness being host cell dependent (Pg. 7, bridging para. for cols.), Ultimately, Freudl concludes that an optimally fitted signal peptide must be identified for every individual target protein to allow for optimal extracellular secretion in the chosen host organism (Pg. 8, left col., 1st para) and that it is “almost impossible” to predict in advance which signal peptide will perform best in the context of a given target protein and bacterial expression host (Abstract; Pg. 8, left col., 1st para.)
Fu et al. (2018, Systematic screening of optimal signal peptides for secretory production of heterologous proteins in Bacillus subtilis. J. of Ag. and Food Chem., 66(50), 13141-13151) also teaches that secretory expression of heterologous proteins depends on specific signal peptides and that the optimum signal peptide for one protein is not always the best choice for a different protein (Pg. 13142, right col.) and that existing programs used to predict optimal signal peptides were not reliable (Pg. 13147, right col.). Fu et al. teaches that a positively charged N-domain, a highly hydrophobic H domain, and a peptide cleavage motif at the C-terminus of A-X-A are common properties of effective signal peptides in B. subtilis and that signal peptides having fewer than five hydrophobic residues in the H domain are inefficient for secretion of a protein and that the presence of an amino acid which interrupts a stretch of hydrophobic residues in the H domain is also important for secretory function (Pg. 13149, right col., bottom half).
Degering et al. (found in IDS dated 04/25/2023) teaches it is not possible to predict which signal peptide results in the best secretion for any given target protein (Abstract) and that some signal peptides which were effective for secretion in B. subtilis were not effective in strains of B. licheniformis (Fig. 5B). Degering et al. concludes that the functional ability of signal peptides as it relates to extracellular secretion can “not be predicted a priori” (Pg. 6375, left col., center para.).
Applicant’s claims comprise signal peptides comprising N-terminal regions which have 90% sequence identity to SEQ ID NOs: 10 and 11, however, as stated supra the prior art indicates that alterations in the amino acid sequence of the N terminus which change the net charge or which alter the hydrophobicity of the H region can affect the secretory efficiency of a signal peptide. Applicant has provided no indication of which amino acids in which portions of the N-terminus could be modified while maintaining the functional ability. In fact, in line with teachings of the prior art, Applicant’s specification appears to indicate that a structural modification of a single amino acid in the C-terminal region results in a modified signal peptide which completely eliminates the functional ability of the signal peptide in extracellular secretion (See SEQ ID NOs: 82-83 in Table 4). Additionally, it is noted that Applicant has reduced to practice signal peptides having C-terminus amino acid residues of SEQ ID NOs 13-30 combined with the N-terminal region of S237 signal peptide (SEQ ID NO: 11) for the VHH 1ZVY. However, for the VHH 5IMM, Applicant has only reduced to practice signal peptides having C-terminus amino acid residues of SEQ ID NOs 13, 15-18 and 23, which share a common motif of either GGA or GGA as X1-X3, combined with the N-terminal region of yncM signal peptide (SEQ ID NO: 10) (see Table 3). Further, similar to the existing art teaching various effects of signal peptides on secretion based on the host cell, Applicant’s specification indicates that a wildtype S237 signal peptide was unable to produce the VHH 1ZVY in a B. subtilis DprΔsigF strain, requiring the use of a different B. subtilis strain (DprΔsigFΔrecA) for the control signal peptide in production of VHH 1ZVY (See Example 2 and Table 3).
Applicant has claimed a genus of nucleic acid constructs comprising a genus of modified signal peptides comprising a genus of 6-mers of C-terminus amino acid sequences linked to a genus of N-terminal regions which are 90% identical to SEQ ID NOs: 10 or 11 which can be used for expression and extracellular secretion of a genus of VHHs in a genus of host Bacillus. However, the specification only identifies specific modified signal peptides comprising combinations of C- and N- termini which can be used for extracellular expression of a VHH in a single Bacillus subtilis host strain (Table 3). Regardless of how the specific sequences of modified signal peptides were derived by Applicant, based on the teachings of the prior art, any chosen signal peptide is not guaranteed to function for extracellular secretion of any VHH in any Bacillus bacterium. Because Applicant has provided no manner a priori to predict which modified signal peptides can be used for extracellular expression of which VHH, the genus of nucleic acid constructs comprising a genus of modified signal peptides which can be used for expression and extracellular secretion of a genus of a VHH in a genus of Bacillus host cells as claimed by Applicant cannot be predictably chosen or used by the ordinary artisan.
CONCLUSION
Therefore, the Examiner concludes that there is insufficient written description of the instantly claimed genus of nucleic acid constructs for the expression and extracellular secretion of a VHH in a genus of Bacillus bacteria comprising a genus of first polynucleotides encoding a VHH and a genus of second polynucleotides encoding a modified signal peptide comprising the amino acid residues of X1X2X3X4X5X6 at the final 6 positions of the C terminus where X1 is G, P, or A; X2 is G; X3 is P, S, or A and X1X2X3 are not GGP; X4 is A; X5 is S, H, or F; and X6 wherein the N terminal region consists of an amino acid sequence of SEQ ID NO: 10 or 11 or an amino acid sequence having at least 90% sequence identity thereto. Specifically, there is limited description of the structure-function relationship between the claimed genus of polynucleotides encoding the modified signal peptide and their ability to function in a nucleic acid construct for expression and extracellular secretion of a VHH in any Bacillus bacteria and the Examiner further concludes that a skilled artisan would find that the specification inadequately describes the claimed genus of nucleic acid constructs for expression and extracellular secretion of a VHH in any Bacillus host.
Claim Rejections - 35 USC § 112(a) - Enablement
Claims 1-4, 7, 11-15, and 18-19 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 modified signal peptide having a specific amino acid sequence for use in expression and extracellular secretion of a specific VHH in B. subtilis, does not reasonably provide enablement for a nucleic acid construct for expression and extracellular secretion of a VHH comprising any modified signal peptide having amino acid residues of X1X2X3X4X5X6 at the final 6 positions of the C terminus where X1 is G, P, or A; X2 is G; X3 is P, S, or A and X1X2X3 are not GGP; X4 is A; X5 is S, H, or F; and X6 is A wherein the N-terminal region consists of an amino acid sequence of SEQ ID NO: 10 or 11 or an amino acid sequence having at least 90% sequence identity thereto which can be used in any Bacillus host. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
SCOPE OF THE INVENTION
The breadth of the claims encompasses a genus of nucleic acid constructs for expression and secretion of a VHH comprising a modified signal peptide having an amino acid sequence of X1X2X3X4X5X6 at the final 6 positions of the C terminus where X1 is G, P, or A; X2 is G; X3 is P, S, or A and X1X2X3 are not GGP; X4 is A; X5 is S, H, or F; and X6 is A and an N-terminal region consisting of an amino acid sequence of SEQ ID NO: 10 or 11 or an amino acid sequence having at least 90% sequence identity thereto which can be used in a Bacillus host cell in order to produce a VHH via extracellular secretion. As discussed supra, the specification fails to describe the genus of modified signal peptides which could be used for expression and extracellular secretion of a VHH in any Bacillus and would require undue experimentation to discover these modified signal peptides. The specification only discloses and provides guidance for a limited genus of C-terminus amino acid sequences which can be used with a limited genus of N-terminal regions for expression and extracellular secretion of a limited genus of VHHs in a single species of B. subtilis.
Independent claim 1 encompasses a nucleic acid construct for the expression and extracellular secretion of a genus of antibody-related molecules which are a variable domain of a heavy chain of heavy chain antibody (VHH) from a genus of Bacillus bacteria comprising a genus of first polynucleotides encoding the antibody-related molecules and a genus of second polynucleotides encoding a modified signal peptide comprising the amino acid residues of X1X2X3X4X5X6 at the final 6 positions of the C terminus where X1 is G, P, or A; X2 is G; X3 is P, S, or A and X1X2X3 are not GGP; X4 is A; X5 is S, H, or F; and X6 is A and wherein a region of the N-terminus to position 7 of the modified signal peptide consists of a genus of amino acid sequences of SEQ ID NO: 10 or 11 or an amino acid sequence having at least 90% identity thereto, while the specification only discloses a fixed number of species of 6-mers of amino acids at the C-terminus of the modified signal peptide, a fixed number of species of the N-terminal sequences having 90% or greater identity to SEQ ID NOs: 10 or 11, which can be used in a fixed number of combinations, and a fixed number of Bacillus strains.
Dependent claim 2 encompasses a genus of polynucleotides encoding a modified signal peptide comprising the amino acid residues of X1X2X3X4X5X6 at the final 6 positions of the C terminus where X1 is G, P, or A; X2 is G; X3 is P or S; X4 is A; X5 is S or H; and X6 is A.
Dependent claims 3-4 encompass a genus of polynucleotides encoding a modified signal peptide comprising the amino acid residues having SEQ ID NOs: 13-30.
Dependent claim 7 encompasses a genus of modified signal peptides consisting of an amino acid sequence of SEQ ID NOs: 31-35, (i.e. an N-terminal region of SEQ ID NO: 10 and C-terminus of SEQ ID NOs: 25-28 or N-terminal region of SEQ ID NO: 11 and C-terminus of SEQ ID NO: 15).
Dependent claims 11-13 encompasses a genus of promoters and expression vectors and promoters comprising the nucleic acid construct of claim 1.
Dependent claim 14 encompasses a genus of Bacillus bacteria comprising the nucleic acid construct of claim 1.
Dependent claim 15 encompasses a genus of methods of producing an antibody-related molecule comprising culturing the Bacillus of claim 14 and collecting the extracellularly secreted antibody-related molecule.
Dependent claim 18 encompasses a genus a nucleic acid constructs of claim 1 wherein the N-terminal region consists of an amino acid sequence of SEQ ID NO: 11 or an amino acid sequence having 90% identity thereto and wherein X1-X6 consists of the amino acid sequence of an of SEQ ID NOs: 13-30.
Dependent claim 19 encompasses a genus a nucleic acid constructs of claim 1 wherein the N-terminal region consists of an amino acid sequence of SEQ ID NO: 10 or an amino acid sequence having 90% identity thereto and wherein X1-X6 consists of the amino acid sequence of an of SEQ ID NOs: 13, 15-18, or 23.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
ACTUAL REDUCTION TO PRACTICE
The specification does not provide guidance for or a working example for modified signal peptides with C-termini sequences other than SEQ ID NOs: 13-30 and N-termini other than SEQ ID NOs: 10 and 11. Additionally, no working examples were provided for secretion of an antibody-related molecule that is not a VHH in a host other than B. subtilis DprΔsigF. The absence of working examples directed to other modified signal peptides which can be used for extracellular secretion of an antibody-related molecule in any Bacillus necessitates further experimentation. Therefore, the specification does not provide sufficient guidance on how to make and use the full scope of the modified signal peptide for use in expression and secretion of an antibody-related molecule in a Bacillus host as claimed.
In regard to independent claims 1 and dependent claims 2-4 encompassing a nucleic acid construct for the expression and extracellular secretion of a VHH from a Bacillus bacteria comprising a genus of first polynucleotides encoding a VHH and a genus of second polynucleotides encoding a modified signal peptide comprising the amino acid residues of X1X2X3X4X5X6 at the final 6 positions of the C terminus and an N-terminus of the modified signal peptide consisting of a genus of amino acid sequences of SEQ ID NO: 10 or 11 or an amino acid sequence having at least 90% identity thereto, Applicant discloses a limited number of modified signal peptides comprising specific amino acid residues (SEQ ID NO: 13-30, 82-84; see Tables 3 and 4) which are linked with N terminal regions having 100% sequence identity to SEQ ID NO: 10 (yncM) or SEQ ID NO: 11 (S237) for expression of two VHHs, 1ZVY and 5IMM, in a single Bacillus subtilis Dpr9 ΔsigF strain (See Table 3). It is noted that while Applicant has disclosed signal peptide combinations of the N-terminal region of SEQ ID NO: 11 with C-terminus regions of SEQ ID NOs: 13-30 and 82-84, Applicant has only disclosed signal peptide combinations of N-terminal region of SEQ ID NO: 10 with C-terminus regions of SEQ ID NO: 13, 15-18 and 23.
In regard to dependent claim 7 encompassing a genus of modified signal peptides consisting of an amino acid sequence of SEQ ID NOs: 31-35, (i.e. an N-terminal region of SEQ ID NO: 10 and C-terminus of SEQ ID NOs: 25-28 or N-terminal region of SEQ ID NO: 11 and C-terminus of SEQ ID NO: 15) which can be used for expression and extracellular secretion of a VHH in a Bacillus bacterium, Applicant has disclosed extracellular secretion of VHH in B. subtilis.
In regard to dependent claims 11-13, encompassing a genus of vectors and promoters comprising the nucleic acid construct of claim 1, as stated above Applicant discloses a limited number of nucleic acid constructs of claim 1.
In regard to dependent claims 14 and 15, encompassing a genus of host cells which are Bacillus bacteria comprising the nucleic acid construct of claim 1 and a method of producing an antibody-related molecule comprising culturing the Bacillus of claim 14, as stated above, Applicant discloses a limited number of antibody related molecules (i.e., VHHs 1ZVY and 5IMM, Table 3), a limited number of nucleic acid constructs of claim 1 and also a limited number of Bacillus host cells, specifically a Bacillus subtilis Dpr9 ΔsigF strain.
In regard to dependent claim 18, encompassing a genus of a nucleic acid constructs of claim 1 wherein the N-terminal region consists of an amino acid sequence of SEQ ID NO: 11 or an amino acid sequence having 90% identity thereto and wherein X1-X6 consists of the amino acid sequence of an of SEQ ID NOs: 13-30, as stated above, Applicant discloses N terminal regions having 100% sequence identity to SEQ ID NO: 11.
In regard to dependent claim 19, encompassing a genus of a nucleic acid constructs of claim 1 wherein the N-terminal region consists of an amino acid sequence of SEQ ID NO: 10 or an amino acid sequence having 90% identity thereto and wherein X1-X6 consists of the amino acid sequence of an of SEQ ID NOs: 13, 15-18, or 23, as stated above, Applicant discloses N terminal regions having 100% sequence identity to SEQ ID NO: 10.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
Brockmeier et al. (found in IDS dated 04/25/2025) teaches that the most effective signal peptide for use in secretion of one protein is not necessarily the most effective or even a sufficient signal peptide for secretion of a different target protein in B. subtilis and that signal peptides must be optimized based on the individual protein of interest which is to be secreted (Abstract; Fig 5; Pg. 399, left col. 2nd para.). Additionally, Brockmeier et al. teaches that known programs which purport to predict optimal signal peptides for heterologous protein secretion are unreliable (Table 1, Pg. 399, left col., 3rd para.). Further, Brockmeier et al. teaches that the N-terminal region of the protein also plays a role in the secretion efficiency and that optimal interaction between signal peptide and target protein for secretion is critical (Pg. 399, left col., 1st para.). Brockmeier et al. ultimately concludes that secretion efficiency for a protein in B. subtilis is determined by “a complex pattern of events.” (Pg. 399, right col. 3rd para.). Thus, Brockmeier et al. teaches that determining which signal peptide can be used for extracellular secretion in B. subtilis is unpredictable and that effective signal peptides for extracellular secretion much be chosen/optimized based on the specific target protein (Abstract).
Freudl et al. (2018, Signal peptides for recombinant protein secretion in bacterial expression systems. Microbial Cell Factories, 17(1), 52) teaches that modifications to signal peptides in the N-terminal region which result in alterations of the net charge of the N-terminal region can either increase or decrease secretion efficiency based on the signal peptide being modified and target protein being secreted (Pg. 6, right col., last para. and Pg. 7, left col. 1st para.). Similarly, Freudl et al. teaches that amino acid alterations in the central H-region can also influence effectiveness of a signal peptide with effectiveness being host cell dependent (Pg. 7, bridging para. for cols.), Ultimately, Freudl concludes that an optimally fitted signal peptide must be identified for every individual target protein to allow for optimal extracellular secretion in the chosen host organism (Pg. 8, left col., 1st para) and that it is “almost impossible” to predict in advance which signal peptide will perform best in the context of a given target protein and bacterial expression host (Abstract; Pg. 8, left col., 1st para.). Thus, Freudl teaches that is it similarly unpredictable to choose a signal peptide which can be used to express any target protein in any host cell.
Fu et al (2018, Systematic screening of optimal signal peptides for secretory production of heterologous proteins in Bacillus subtilis. J. of Ag. and Food Chem., 66(50), 13141-13151) also teaches that secretory expression of heterologous proteins depends on specific signal peptides and that the optimum signal peptide for one protein is not always the best choice for a different protein (Pg. 13142, right col.) and that existing programs used to predict optimal signal peptides were not reliable (Pg. 13147, right col.). Fu et al. teaches that a positively charged N-domain, a highly hydrophobic H domain, and a peptide cleavage motif of AXA are common properties of effective signal peptides in B. subtilis and that signal peptides having fewer than five hydrophobic residues in the H domain are inefficient for secretion of a protein and that the presence of an amino acid which breaks up a stretch of hydrophobic residues in the H domain is also important for secretory function (Pg. 13149, right col., bottom half). Therefore, Fu et al similarly teaches that selecting an effective signal peptide is unpredictable and that various amino acid modifications to signal peptides can alter secretory efficacy.
Degering et al. (found in IDS dated 04/25/2023) teaches it is not possible to predict which signal peptide results in the best secretion for any given target protein (Abstract) and that some signal peptides which were effective for secretion in B. subtilis were not effective in strains of B. licheniformis (Fig. 5B). Degering et al. concludes that the functional ability of signal peptides as it relates to extracellular secretion can “not be predicted a priori” (Pg. 6375, left col., center para.). Degering et al. teach selection of signal peptides for specific host cells is also unpredictable.
Applicant’s claims comprise signal peptides comprising N-terminal regions which have 90% sequence identity to SEQ ID NOs: 10 and 11, however, as stated supra the prior art indicates that alterations in the amino acid sequence of the N terminus which change the net charge or which alter the hydrophobicity of the H region can affect the secretory efficiency of a signal peptide. Applicant has provided no indication of which amino acids in which portions of the N-terminus could be modified while maintaining the functional ability. In fact, in line with teachings of the prior art, Applicant’s specification appears to indicate that a structural modification of a single amino acid in the C-terminal region results in a modified signal peptide which eliminates the functional ability of the signal peptide in extracellular secretion (See SEQ ID NOs: 82-83 in Table 4). Additionally, it is noted that Applicant has reduced to practice signal peptides having C-terminus amino acid residues of SEQ ID NOs 13-30 combined with the N-terminal region of S237 signal peptide for the VHH 1ZVY. However, for the VHH 5IMM, Applicant has only reduced to practice signal peptides having C-terminus amino acid residues of SEQ ID NOs 13, 15-18 and 23, which share a common motif of either GGA or GGA as X1-X3, combined with the N-terminal region of yncM signal peptide (see Table 3). Further, similar to the existing art supporting effects on secretion based on the host cell, Applicant’s specification indicates that a wildtype S237 signal peptide was unable to produce the VHH 1ZVY in a B. subtilis DprΔsigF strain, requiring the use of a different B. subtilis strain (DprΔsigFΔrecA) for the control signal peptide in production of VHH 1ZVY (See Example 2 and Table 3). Thus, the prior art as well as Applicant’s disclosure appears to provide evidence that determining which modified C-terminus of a signal peptide can be used with which N-terminal region for expression of which antibody-related molecule in which host cell is unpredictable.
In light of the above factors, Applicant provides enablement for a limited genus of modified signal peptides having a limited genus of C-termini amino acid sequences (SEQ ID NOs: 13-30) which can be used in limited combinations with a limited genus of N-terminal regions (SEQ ID NOs: 10 and 11). Further Applicant provides enablement for use of the modified signal peptides with a limited genus of antibody-related molecules which are VHHs and in a limited genus of host cells which are B. subtilis.
CONCLUSION
In conclusion, since the art teaches that success of choosing a signal peptide which can be used for extracellular secretion of any antibody-related molecule in any host cell is highly unpredictable and must be individually chosen/optimized for specific target proteins and specific host cells and the specification does not provide ample guidance as to which modified signal peptide could be used with respect to achieving the unexpected results, one would be burdened with undue experimentation as to which modified signal peptide could be used with which antibody-related molecule in which host cell in order to produce an antibody-related molecule of interest via extracellular secretion. In conclusion, given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is required to make and use the invention beyond the scope of the limited genus of C-terminal amino acid sequences which can be used with the limited genus of N-terminal regions in the specific combinations (N terminus of SEQ ID NO: 11 with C-termini of SEQ ID NOs: 13-30 and N-terminus of SEQ ID NO: 10 with C-terminus of SEQ ID NOs: 13, 15-18, and 23) which can be used to express and secrete the limited genus of VHHs in the limited genus of a B. subtilis host strain for which Applicant is enabled.
Response to Arguments
Applicant's arguments filed June 16, 2026 have been fully considered but they are not persuasive.
Applicant traverses that the rejection of claims 1-7 and 9-15 under 35 U.S.C. 112(a) for written description and enablement. Applicant asserts on Pg. 6 that the amendments to claim 1 which recite that the N-terminus consists of an amino acid sequence of SEQ ID NO: 10 or 11 or an amino acid sequence having at least 90% identity thereto is sufficiently described and enabled. Applicant similarly asserts on Pg. 6 that the C-termini as recited in claim 1 are sufficiently described an enabled and that Applicant has provided working embodiments of 18 of 27 possible amino acid sequences as recited in claim 1 and that 75% of the possible C termini combinations were tested and result in secretion of a VHH. Applicant further asserts on Pg. 7 that the amendment to claim 1 to recite extracellular expression and secretion of an antibody related molecule which is a VHH is sufficiently described and enabled based on the common framework of VHHs and Applicant’s working examples showing extracellular secretion of 1ZVY and 5IMM.
Applicant’s traversal has been fully considered but is not fully persuasive.
Applicant has canceled claims 5-6 and 9-10 rendering the rejection of those claims moot. Although Applicant’s amendment to claim 1 serves to limit the instantly claimed nucleic acid construct, based on the prior art, there remains a significant amount of unpredictability in the scope of the claimed nucleic acid constructs and their ability to function as signal peptides for extracellular secretion of an antibody-related molecule for any Bacillus bacterium. As detailed in the 112a rejections above, the prior art indicates that choosing a signal peptide for use in extracellular secretion in a host cell is highly complex and unpredictable and must be optimized based not only on the specific signal peptide, but also the heterologous protein to be secreted as well as the host cell.
Although Applicant’s amendment to claim 1 narrows the specific N-terminal region to sequences having at least 90% sequence identity to SEQ ID NO: 10 or 11, Applicant has not provided any guidance as to which 10% of the amino acid sequences in which portion of the N-terminus of SEQ ID NOs: 10 and 11 could be altered without affecting the functional ability of the signal peptide and the prior art indicates that alterations of the net charge and hydrophobic regions of the N-terminus can drastically affect functional secretory ability. Similarly, although Applicant has reduced to practice 18 of the 24 possible amino acid sequences of the C terminus as recited in claim 1, Applicant’s instant specification indicates that a single amino acid change in the C terminus is able to eliminate all secretory ability of a signal peptide (See SEQ ID NOs 82-84, Tables 3 and 4). Therefore, it is not predictable whether the remaining 25% of the signal peptides would retain functional ability in combination with either or both of the N-termini sequences and, although the A-X-A motif of the C-terminus is known to be important, Applicant has provided no guidance as to which of the other positions or motifs in the amino acid sequence of the C terminus are important for functional ability of the signal peptide. Additionally, although Applicant has shown secretory effect for C termini having SEQ ID NOs: 13-30 when linked with an N-terminus of SEQ ID NO: 11, when using an N-terminus of SEQ ID NO: 10 Applicant has shown secretory effect for only a subset of C-termini (SEQ ID NOs; 13, 15-18, and 23) which all appear to share a GGA or GGS motif in positions X1-X3. Given the unpredictability in the art surrounding selection of functional signal peptides and the lack of guidance in the instant specification, a skilled artisan could not readily predict which signal peptide combination of N- and C- termini could be used for extracellular secretion of a heterologous protein in any Bacillus host.
With regard to the host cell and antibody related molecule, Applicant has limited the host cell to Bacillus bacterium; the instant specification provides exemplary strains of B. subtilis, B. cereus, B. thuringiensis, B. megaterium, B. amyloliquefaciens, B. pumilus, B. liqueniformis (interpreted as B. licheniformis), and mutant strains thereof (Para. [0024]); and Applicant has reduced to practice some of the instantly claimed signal peptides in B. subtilis. As detailed above, the prior art indicates that there can be significant differences in functional ability of the same signal peptide in Bacillus strains therefore a skilled artisan could not predict that a signal peptide which is functional in one Bacillus host would function in all Bacillus hosts. Applicant has limited the antibody-related molecule to a VHH as recited in claim 1, reduced to practice VHHs of 1ZVY and 5IMM and provided a sequence alignment of the VHHs as listed in Table 1 of the Specification (Pg. 7) showing the conserved framework of VHHs. Thus, the Examiner concludes that the genus of VHHs which could be secreted by the instantly claimed signal peptides in B. subtilis are sufficiently described and enabled.
Claim Rejections - 35 USC § 112(b)
Claim 15 is 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites the limitation "a method for producing an antibody related molecule" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim as claim 15 recites culturing the Bacillus bacterium of claim 14 which comprises the nucleic acid construct of claim 1 which recites that the antibody related molecule is a VHH. Appropriate correction is required. It is recommended that Applicant amend claim 15 to recite a method of producing an antibody related molecule which is a VHH, similar to claim 1.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631
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