DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 70-77 and 79-90 are pending in the application.
Applicant’s amendment to the claims, filed January 27, 2026, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s amendment to the specification, filed January 27, 2026, is acknowledged.
Applicant’s remarks filed January 27, 2026 in response to the non-final rejection filed October 27, 2025 are acknowledged and have been fully considered.
Claims 62-66 and 78 are canceled by claim amendment filed January 27, 2026 and rejections previously applied to these clams are withdrawn.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Restriction/Election
In response to a requirement for restriction/election filed August 13, 2025, applicant elected without traverse the invention of Group I, corresponding to pending claims 70-77 and 79-90, drawn to the technical feature of a genetically modified fungal host cell, and the species of a polypeptide comprising, consisting essentially of, or consisting of an amino acid sequence corresponding to the amino acid sequence of IdtA from Epichloë var. lolii strain AR37, or corresponding to a polypeptide encoded by the idtA gene from Epichloë festucae var. lolii strain AR37, SEQ ID NO: 3, SEQ ID NO: 52, and SEQ ID NO: 53, variants and fragments thereof, a polypeptide involved in the production of one or more janthitrem compound, and a polypeptide comprising an enzymatic activity having as its substrate terpendole I or as its substrate or its product a compound of any one of formulae Ito VIII in the reply filed September 4, 2025.
Specification/Informalities
The objection to the specification for embedded hyperlinks is withdrawn in view of applicant’s amendment to the specification to amend the disclosed websites to the top-level domain name.
Claim Objections
The objections to claims 72 and 80 are withdrawn in view of applicant’s amendment to remove periods from the body of claims 72 and 80 and to recite “90% amino acid sequence identity” in claim 72.
Claims 79-81 are objected to and in the interest of substantially improving claim form, it is suggested that claim 79 be amended to recite (with markings to show changes made) “A population of cells comprising the genetically modified fungal host cell of claim 77 andpopulation of cells
Claim Rejections - 35 USC § 112(b)
The rejection of claims 75 and 76 as lacking antecedent basis for "the pathway for synthesizing a compound of formula II from a carbon source…” is withdrawn in view of applicant’s amendment to replace “the” with “a” in the noted phrase.
The rejection of claims 79-81 as being confusing because an Epichloë cell is not known in the art to comprise one or more plant cells is withdrawn in view of applicant’s amendment to claim 79.
The rejection of claim 80 for lacking antecedent basis in the recitation of “the one or more plant cells” is withdrawn in view of applicant’s amendment to claim 81 to depend from claim 79.
The rejection of claim 81 for lacking antecedent basis in the recitation of "said population” is withdrawn in view of applicant’s amendment to claim 81 to depend from claim 79.
Claims 70-77 and 79-90 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. This rejection has been modified from its previous version to address applicant’s amendments to the claims.
Claims 70 (claims 71-77, 79-83, 85, 87, 89, and 90 dependent therefrom), 84, 86, and 88 are indefinite in the recitation of “idtA gene” because it is unclear from the specification and the claims as to the scope of genes encompassed by “idtA gene.” The specification discloses "[t]he gene idtA encodes an acyltransferase homolog, which is predicted to convert epoxy-janthitriol to epoxy-janthitrem I and epoxy-janthitrem III to epoxy- janthitrem IV by the addition of an acyl group" (p. 34, lines 33-35). However, given that the recited activity is merely predicted, it is unclear from the specification as to whether or not the polypeptide encoded by an idtA gene is or is not required to convert epoxy-janthitriol to epoxy-janthitrem I and epoxy-janthitrem III to epoxy-janthitrem IV by the addition of an acyl group. As such, it is unclear as to the intended scope of “idtA gene.” In the interest of advancing prosecution and clarifying the intended scope of “idtA gene,” applicant may consider an amendment to claim 70 to recite the intended enzymatic activity of the polypeptide encoded by the idtA gene, e.g., acyltransferase activity converting epoxy-janthitrem III to epoxy-janthitrem IV.
RESPONSE TO REMARKS: Applicant argues the rejection is obviated by the amendment to claim 70 and the substantial discussion of the specification regarding an "idtA gene.”
Applicant’s arguments are not found persuasive. Applicant fails to elaborate on the limitation(s) of claim 70 and the “substantial discussion” of the specification for one of skill in the art to determine the intended meaning and scope of an “idtA gene.” In this case, the specification arbitrarily assigns the designation “idtA gene” and neither the specification nor the prior art of record provides distinguishing characteristics such that one of skill in the art could identify the intended scope of genes encompassed by an “idtA gene.”
Claim 76 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. This rejection has been modified from its previous version to address applicant’s amendments to the claims.
Claim 76 is indefinite in the recitation of “a compound of formula II” because it is unclear as to whether “a compound of formula II” has the structure represented by formula II of claim 75 or some other structure(s). If applicant intends for the recited formula II to refer to a formula disclosed in the specification, according to MPEP 2173.05(s), where possible, claims are to be complete in themselves…Incorporation by reference is a necessity doctrine, not for applicant’s convenience, and in accordance with MPEP 2173.05(s), the recited formula II structure must be expressly recited in the claim and not incorporated by reference.
RESPONSE TO REMARKS: Applicant argues claim 76 has been amended to recite the formula or the formula is identified in the claim from which it depends.
Applicant’s argument is not found persuasive because neither claim 76 nor the claims from which it depends set(s) forth the structure represented by formula II.
Claim Rejections - 35 USC § 112(a)
Claims 70-77 and 79-90 are rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention. This rejection has been modified from its previous version to address applicant’s amendments to the claims.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the 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.”
For claims drawn to a genus, MPEP § 2163 states 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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
MPEP § 2163 further states that “[s]atisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’"
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163.
Claim 70 (claims 71-77 and 79-90 dependent therefrom) recites a genus of genetically modified fungal host cells capable of producing one or more indole diterpene compounds, wherein the fungal host cell comprises at least one genetic modification in an idtA gene that reduces or prevents the production or activity of an idtA gene product, wherein the production or amount of one or more epoxy-janthitrem compounds is decreased when compared to a fungal host cell or fungal organism of the same species in which such a genetic modification in an idtA gene is not present.
Regarding the recited “idtA gene,” as stated above, the specification discloses “[t]he gene idtA encodes an acyltransferase homolog, which is predicted to convert epoxy-janthitriol to epoxy-janthitrem I and epoxy-janthitrem III to epoxy-janthitrem IV by the addition of an acyl group” (p. 34, lines 33-35). However, given that the recited activity is merely predicted, it is unclear from the specification and prior art of record as to whether or not the polypeptide encoded by an idtA gene is or is not required to convert epoxy-janthitriol to epoxy-janthitrem I and epoxy-janthitrem III to epoxy-janthitrem IV by the addition of an acyl group. The language of claim 70 indicates that the idtA gene product is related to production or amount of one or more undefined epoxy-janthitrem compounds, however, the specification arbitrarily assigns the designation “idtA gene” without providing distinguishing characteristics such that one of skill in the art could identify the intended scope of genes in other fungi that are considered to be “idtA” genes.
The structures of the recited “one or more epoxy-janthitrem compounds” in claim 70 are unlimited.
Claim 71 is drawn to the genetically modified fungal host cell as claimed in claim 70 comprising at least one genetic modification associated with altered regulation or production of one or more gene products encoded by a gene selected from the group consisting of idtB, idtC, idtD, idtF, idtG, idtK, idtM, idtO, idtP, and idtQ.
The genetic modifications to at least one genetic modification associated with altered regulation or production of one or more gene products encoded by a gene selected from the group consisting of idtB, idtC, idtD, idtF, idtG, idtK, idtM, idtO, idtP, and idtQ is/are unlimited.
The specification discloses the actual reduction to practice of the following species of the claimed host cells – an Epichloë host cell having a deletion of a gene encoding the polypeptide of SEQ ID NO: 3 or 53 and optionally transformed or transfected with a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 6, 9, 17, 19, 21, 23, 50, 51, 70, 71, 72, 73, or 74.
The reference of Spangenberg et al. (WO 2018/027275 A1; cited on the IDS filed November 2, 2022) discloses that genes for epoxy-janthitrem production are present on gene clusters 3 and 4 of Epichloe festucae var. lolii NEA12 but were not expressed in Epichloe festucae var. lolii (SE) (pp. 25-27). Given that genes for epoxy-janthitrem production may or may not even be present among strains of Epichloe festucae var. lolii, one of skill in the art would have recognized unpredictability in the art that a fungal cell would even comprise genes involved in epoxy-janthitrem production.
Given the absence of distinguishing characteristics of an “idtA gene” in other fungal cells in the specification and prior art of record, and given that claim 70 non-specifically correlates the genetic modification of any fungal gene considered to be an “idtA gene” with decreased production or amount of any epoxy-janthitrem compound, the recited genus of genetically modified fungal host cells of claim 70 is considered to encompass widely variant species. In this case, one of skill would not accept the disclosure of the single disclosed species of an Epichloë host cell having a deletion of a gene encoding the polypeptide of SEQ ID NO: 3 or 53 and optionally transformed or transfected with a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 6, 9, 17, 19, 21, 23, 50, 51, 70, 71, 72, 73, or 74 as being representative of other genetically modified fungal host cells as encompassed by the claims. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
RESPONSE TO REMARKS: Applicant argues the rejection is obviated by amendment to recite “"genetically modified fungal host cell” combined with the disclosure of the specification, particularly disclosure related to genetic modifications to introduce heterologous genetic material into a fungal host cell and to have any gene products encoded by genes present within that genetic material expressed in fungi.
Applicant’s arguments are not found persuasive. As stated above, the specification only provides a predicted activity of the polypeptide encoded by an “idtA gene” and there is unpredictability that a fungal cell will even comprise genes including an “idtA gene” involved in epoxy-janthitrem production and thus, it appears applicant relies on one of skill in the art to perform additional experimentation to identity and confirm the enzymatic activity or activities of an “idtA gene” in fungal host cells and correlate its activity or activities with the production or amount of one or more epoxy-janthitrem compounds. However, according to MPEP 2163.II.3, “An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed”. In this case, other than the single disclosed species as noted above, neither the specification nor the prior art of record provides distinguishing characteristics of any other fungal “idtA gene,” there is unpredictability as to whether a fungal cell will even comprise genes involved in epoxy-janthitrem production comprise, and given that claim 70 non-specifically correlates the genetic modification of any fungal gene considered to be an “idtA gene” with decreased production or amount of any epoxy-janthitrem compound, the single disclosed species fails to be representative other fungal cells as encompassed by the claims and the specification fails to adequately describe the claimed invention.
Claims 70-77 and 79-90 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for an Epichloë host cell having a deletion of a gene encoding the polypeptide of SEQ ID NO: 3 or 53 and optionally transformed or transfected with a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 6, 9, 17, 19, 21, 23, 50, 51, 70, 71, 72, 73, or 74, does not reasonably provide enablement for all genetically modified fungal host cells as broadly encompassed by the claims. 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/or use the invention commensurate in scope with these claims.
“The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
The nature of the invention: According to the specification, “there is a need for ways of providing one or more beneficial indole diterpene compounds, without concomitant or with reduced provision of one or more detrimental or undesirable indole diterpene compounds. It is therefore an object of the invention to provide one or more host cells capable of producing one or more epoxy-janthitrem compounds” (p. 1, line 40 to p. 2, line 2).
The breadth of the claims: Claim 70 (claims 71-77 and 79-90 dependent therefrom) recites a genetically modified fungal host cell capable of producing one or more indole diterpene compounds, wherein the fungal host cell comprises at least one genetic modification in an idtA gene that reduces or prevents the production or activity of an idtA gene product, wherein the production or amount of one or more epoxy-janthitrem compounds is decreased when compared to a fungal host cell or fungal organism of the same species in which such a genetic modification in an idtA gene is not present.
Regarding the recited “idtA gene,” as stated above, the specification discloses “[t]he gene idtA encodes an acyltransferase homolog, which is predicted to convert epoxy-janthitriol to epoxy-janthitrem I and epoxy-janthitrem III to epoxy-janthitrem IV by the addition of an acyl group” (p. 34, lines 33-35). However, given that the recited activity is merely predicted, it is unclear from the specification and prior art of record as to whether or not the polypeptide encoded by an idtA gene is or is not required to convert epoxy-janthitriol to epoxy-janthitrem I and epoxy-janthitrem III to epoxy-janthitrem IV by the addition of an acyl group. The language of claim 70 indicates that the idtA gene product is related to production or amount of one or more undefined epoxy-janthitrem compounds, however, the specification arbitrarily assigns the designation “idtA gene” without providing distinguishing characteristics such that one of skill in the art could identify the intended scope of genes in other fungi that are considered to be “idtA” genes.
The structures of the recited “one or more epoxy-janthitrem compounds” in claim 70 are unlimited.
Claim 71 is drawn to the genetically modified fungal host cell as claimed in claim 70 comprising at least one genetic modification associated with altered regulation or production of one or more gene products encoded by a gene selected from the group consisting of idtB, idtC, idtD, idtF, idtG, idtK, idtM, idtO, idtP, and idtQ.
The genetic modifications to at least one genetic modification associated with altered regulation or production of one or more gene products encoded by a gene selected from the group consisting of idtB, idtC, idtD, idtF, idtG, idtK, idtM, idtO, idtP, and idtQ is/are unlimited.
The state of the prior art; The level of one of ordinary skill; and The level of predictability in the art: According to MPEP 2164.03, “…what is known in the art provides evidence as to the question of predictability” and “[I]f one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art.” The reference of Spangenberg et al. (WO 2018/027275 A1; cited on the IDS filed November 2, 2022) discloses that genes for epoxy-janthitrem production are present on gene clusters 3 and 4 of Epichloe festucae var. lolii NEA12 but were not expressed in Epichloe festucae var. lolii (SE) (pp. 25-27). Given that genes for epoxy-janthitrem production may or may not even be present among strains of Epichloe festucae var. lolii, one of skill in the art would have recognized unpredictability in the art that a fungal cell would even comprise genes involved in epoxy-janthitrem production.
The amount of direction provided by the inventor and The existence of working examples: The specification discloses the following working example of the claimed fungal host cell – an Epichloë host cell having a deletion of a gene encoding the polypeptide of SEQ ID NO: 3 or 53 and optionally transformed or transfected with a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 6, 9, 17, 19, 21, 23, 50, 51, 70, 71, 72, 73, or 74. Other than this working example, the specification fails to provide direction or guidance regarding the presence and identifying characteristics of an “idtA gene” in other fungal cells.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: While methods of genetic modifications to introduce heterologous genetic material into a fungal host cell were known at the time of the invention, it was not routine in the art to make all fungal host cells as broadly encompassed by the claims.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability as evidenced by the prior art, and the amount of experimentation required to make the invention, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
RESPONSE TO REMARKS: Applicant argues the rejection is obviated by amendment to recite “"genetically modified fungal host cell” combined with the disclosure of the specification, particularly disclosure related to genetic modifications to introduce heterologous genetic material into a fungal host cell and to have any gene products encoded by genes present within that genetic material expressed in fungi.
Applicant’s arguments are not found persuasive. In view of the detailed analysis of the Factors of In re Wands above, particularly that other than the single disclosed working example noted above, neither the specification nor the prior art of record provides guidance or direction regarding the presence and distinguishing characteristics of any other fungal “idtA gene,” there is unpredictability that a fungal cell will even comprise genes involved in epoxy-janthitrem production including an “idtA gene,” and claim 70 non-specifically correlates the genetic modification of any fungal gene considered to be an “idtA gene” with decreased production or amount of any epoxy-janthitrem compound, the specification fails to enable the full scope of the claimed invention.
Claim Rejections - 35 USC § 101
The rejection of claims 70, 71, 73-75, 77, and 79-81 under 35 U.S.C. 101 is withdrawn in view of applicant’s amendment to claim 70 to recite “wherein the fungal host cell comprises at least one genetic modification in an idtA gene that reduces or prevents the production or activity of an idtA gene product, wherein the production or amount of one or more epoxy-janthitrem compounds is decreased when compared to a fungal host cell or fungal organism of the same species in which such a genetic modification in an idtA gene is not present.” The claimed fungal host cell is markedly different from a naturally occurring fungal cell.
Claim Rejections - 35 USC § 102
The rejection of claims 70-77 and 79-81 under 35 U.S.C. 102(a)(1) as being anticipated by Spangenberg et al. (WO 2018/027275 A1; cited on the IDS filed November 2, 2022; hereafter “Spangenberg”) as evidenced by UniProt Database Accession Number J7FIX8 (December 2019, 1 page; cited on Form PTO-892 filed October 27, 2025; hereafter “UniProt J7FIX8”) is withdrawn in view of applicant’s amendment to claim 70 to recite “wherein the fungal host cell comprises at least one genetic modification in an idtA gene that reduces or prevents the production or activity of an idtA gene product, wherein the production or amount of one or more epoxy-janthitrem compounds is decreased when compared to a fungal host cell or fungal organism of the same species in which such a genetic modification in an idtA gene is not present.” Spangenberg does not teach or suggest at least one genetic modification in an idtA gene that reduces or prevents the production or activity of an idtA gene product.
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.
Claims 70-77 and 79-90 are rejected under 35 U.S.C. 103 as being unpatentable over Spangenberg in view of
Saikia et al. (FEBS Lett. 580:1625-1630, 2006; cited on the attached Form PTO-892; hereafter “Saikia”),
Scott et al. (Toxins 5:1422-1446, 2013; cited on the attached Form PTO-892; hereafter “Scott”), and
Giraldo et al. (Transgenic Res. 27:397-407, 2018; cited on the attached Form PTO-892; hereafter “Giraldo”), and as evidenced by
UniProt J7FIX8,
GenBank Database Accession Number QGV56749 (December 2019, 1 page; cited on the attached Form PTO-892; hereafter “GenBank QGV56749”), and
UniProt Database Accession Number J7FK08 (February 2019, 1 page; cited on the attached Form PTO-892; hereafter “UniProt J7FK08”).
As amended, the claims are drawn to a genetically modified fungal host cell capable of producing one or more indole diterpene compounds, wherein the fungal host cell comprises at least one genetic modification in an idtA gene that reduces or prevents the production or activity of an idtA gene product, wherein the production or amount of one or more epoxy-janthitrem compounds is decreased when compared to a fungal host cell or fungal organism of the same species in which such a genetic modification in an idtA gene is not present.
Regarding claims 70 and 77, Spangenberg teaches janthitrems are a class of indole diterprenes produced by a subgroup of endophytes (p. 1, lines 29-30), which provide protection against pasture pests in perennial ryegrass pastures (p. 2, lines 9-10). Spangenberg teaches there is an increasing need to further understand janthitrems and their biosynthesis, as this would provide information useful in manipulating janthitrem production (p. 2, lines 21-23). Spangenberg teaches the identification of the janthitrem biosynthetic gene cluster in the Epichloë endophyte LpTG3/NEA12 genome (p. 3, lines 28-31; pp. 22-23; and Table 2), which comprises gene clusters 1, 2, 3, and 4 (p. 14, lines 11-13; p. 25, lines 17-20). Spangenberg teaches gene cluster 3 comprises a PP02 gene (p. 14, lines 11-13), which is predicted to be associated with janthitrem biosynthesis in Epichloë endophytes (p. 14, lines 19-25; p. 26, lines 17-18; Figure 20) as a membrane-bound O-acyl transferase (p. 16, line 33). Spangenberg teaches the nucleotide sequence of the PP02 gene (Figure 10) and corresponding amino acid sequence (Figure 11). Although Spangenberg does not refer to the PP02 gene as idtA, SEQ ID NO: 6 of Spangenberg encodes the amino acid sequence of instant SEQ ID NO: 3 (see Appendix at pp. 25-27 of the Office action mailed October 27, 2025 for sequence alignment), which is disclosed in the instant specification as the polypeptide encoded by the idtA gene from Epichloë festucae var. lolii AR37 (p. 26, lines 17-18). As such, the PP02 gene of Spangenberg is considered to be the same as the idtA gene in the claims of this application.
Spangenberg does not teach a genetic modification in an idtA gene that reduces or prevents the production or activity of an idtA gene product.
Saikia teaches the cloning and characterization of a cluster of genes from Penicillium paxillin necessary for the biosynthesis of the indole diterpene paxilline (p. 1625, column 2, top). Saikia teaches systematic gene disruption and chemical complementation studies have enabled identification of the enzymes that are needed for paxilline biosynthesis (p. 1625, column 2, top). Saikia teaches ectoptic expression of all or different subsets of paxilline biosynthetic genes in a paxilline-negative deletion mutant that lacks the entire paxilline biosynthetic gene cluster to identify the genes necessary for biosynthesis of a paxilline intermediate (p. 1627, column 1, middle).
Similar to Saikia, Scott teaches paxilline is an indole diterpene synthesized by Penicillium paxilli (p. 1422, Abstract) and teaches a complete functional analysis of the paxilline gene cluster using a combination of experiments including multiple targeted replacement of all identified genes of the paxilline gene cluster (p. 1424, last full paragraph; p. 1426, middle to bottom).
In view of the combined teachings of Spangenberg, Saikia, and Scott, it would have been obvious to one of ordinary skill in the art before the effective filing date to make an Epichloë endophyte NEA12 mutant deleted only for PP02 (idtA) and an Epichloë endophyte NEA12 mutant deleted for the entire janthitrem gene cluster including the PP02 (idtA) gene in order to identify genes necessary for biosynthesis of janthitrem. One would have been motivated to do so because, while Spangenberg teaches a need to understand janthitrems and their biosynthesis, Spangenberg predicts genes and their corresponding roles in janthitrem biosynthesis, Saikia and Scott teach experiments – including systematic gene disruption and chemical complementation studies, ectoptic expression of all or different subsets of biosynthetic genes in a deletion mutant that lacks an entire biosynthetic gene cluster, and multiple targeted replacement of all identified genes of a gene cluster – to identify the genes necessary for biosynthesis of janthitrem and intermediates. One would have expected success because Spangenberg teaches the nucleotide sequence of the PP02 (idtA) gene and Scott teaches experimental methodology for gene deletion based on the nucleotide sequence of a gene (beginning at the bottom of p. 1437).
Regarding claim 71, for reasons stated above, in view of the combined teachings of Spangenberg, Saikia, and Scott, it would have been obvious to make an Epichloë endophyte NEA12 mutant deleted for the entire janthitrem gene cluster, which, according to Spangenberg, also includes a itmG gene (p. 22, lines 11-12; Table 2). Although Spangenberg does not refer to the itmG gene as idtG, Spangenberg teaches the itmG gene of NEA12 encodes a geranylgeranyl diphosphate synthase (p. 24, Table 2; p. 25, lines 27-28) and evidentiary reference UniProt J7FIX8 teaches idtG gene encodes a geranylgeranyl diphosphate synthase. As such, the itmG gene of Spangenberg is considered to be encompassed by idtG gene in instant claim 71 and an Epichloë endophyte NEA12 mutant deleted for the entire janthitrem gene cluster includes a deletion of the idtG gene.
Regarding claim 72, Spangenberg teaches the identification of the janthitrem biosynthetic gene cluster in the Epichloë endophyte LpTG3/NEA12 genome (p. 3, lines 28-31; pp. 22-23; and Table 2), which comprises gene cluster 4 containing a JtmD gene (p. 26, bottom). Evidentiary reference GenBank QGV56749 is cited to show that the amino acid sequence of JtmD is substantially identical but nonetheless distinct from the amino acid sequence of instant SEQ ID NO: 6 (see Appendix for sequence alignment). The instant specification also discloses the idtD gene encodes SEQ ID NO: 6 (p. 26, lines 19-20), instant Figure 1 shows that idtD converts terpendole I to epoxy-janthitriol and converts terpendole J to epoxy-janthitrem III. Given that JtmD is substantially identical but distinct from the amino acid sequence of instant SEQ ID NO: 6, the JtmD of Epichloë endophyte LpTG3/NEA12 is considered to be “heterologous” to an Epichloë endophyte NEA12 mutant deleted only for PP02 (idtA) of the combination of Spangenberg, Saikia, and Scott and converts terpendole I to epoxy-janthitriol and converts terpendole J to epoxy-janthitrem III.
Regarding claims 73 and 74, for reasons stated above, in view of the combined teachings of Spangenberg, Saikia, and Scott, it would have been obvious to make an Epichloë endophyte NEA12 mutant deleted only for the PP02 (idtA) gene and as shown by instant Figures 1A and 1B, such a mutant would still express genes for the production of compounds with structures that are encompassed by formulae IV to VIII. For example, in view of instant Figure 1A, an Epichloë endophyte NEA12 mutant deleted only for the PP02 (idtA) gene would still express genes for production of paxilline, which is encompassed by Formula VII of claim 73.
Regarding claims 75 and 83-88, for reasons stated above, in view of the combined teachings of Spangenberg, Saikia, and Scott, it would have been obvious to make an Epichloë endophyte NEA12 mutant deleted only for the PP02 (idtA) gene and as shown by instant Figure 20, such a mutant would still express genes for the production of compounds with structures that are encompassed by formula II. For example, in view of instant Figure 20, an Epichloë endophyte NEA12 mutant deleted only for the PP02 (idtA) gene would still express genes for production of epoxy-janthitrem intermediates such as epoxy-janthitriol and epoxy-janthitrem III, which are encompassed by Formula II of claim 75 and formulae IIA and IID of claims 85-87, and given the deletion of PP02 (idtA), the intermediates epoxy-janthitriol and epoxy-janthitrem III would accumulate and not be converted to epoxy-janthitrem I and epoxy-janthitrem IV by idtA.
Regarding claim 76, for reasons noted above, it is unclear as to the structure of the compound of formula II in claim 76. Assuming arguendo formula II in claim 76 is the same as formula II in claim 75, for reasons stated above, in view of the combined teachings of Spangenberg, Saikia, and Scott, it would have been obvious to make an Epichloë endophyte NEA12 mutant deleted only for the PP02 (idtA) gene with ectoptic expression of all or different subsets of biosynthetic genes in a deletion mutant that lacks an entire biosynthetic gene cluster, and multiple targeted replacement of all identified genes of a gene cluster to identify the genes necessary for biosynthesis of janthitrem and intermediates and doing so would have resulted in expression of genes for production of epoxy-janthitrem compounds encompassed by formula II of claim 75.
Regarding claims 79-81, Spangenberg teaches that while the presence of janthitrems in perennial ryegrass pastures provides superior protection against a wide range of important pasture pests (p. 2, lines 9-10) and Epichloë endophyte-derived janthitrems have been observed to exhibit bioprotective properties that provide an advantage to pasture (p. 2, lines 17-18), janthitrems including janthitrems A and B can be tremorgenic and cause animals grazing on endophyte infected pastures develop to ataxia, tremors, and hypersensitivity to external stimuli (p. 2, lines 10-14).
Spangenberg teaches a plant inoculated with an endophyte (p. 10, lines 30-33).
Giraldo teaches that alkaloid profiles vary among different endophyte species and strains and development of endophyte strains with optimal alkaloid profiles are important in the livestock industry, noting that it is essential to deliver the specific concentration of alkaloids, to prevent insect attack on plants, but to not affect animal wellbeing (p. 399, column 1, third paragraph).
In view of the combined teachings of Spangenberg, Saikia, Scott, and Giraldo, it would have been obvious to one of ordinary skill in the art to inoculate a perennial ryegrass with the Epichloë endophyte NEA12 mutant of the combination of Spangenberg, Saikia, and Scott. One would have been motivated to do this in order to determine the effects of alkaloid production by such an Epichloë endophyte NEA12 mutant on insect attack and animal wellbeing and for development of an Epichloë endophyte strain with optimal alkaloid profiles. One would have had expected success because Spangenberg taught a plant inoculated with an endophyte.
Regarding claim 82, for reasons stated above, in view of the combined teachings of Spangenberg, Saikia, and Scott, it would have been obvious to make an Epichloë endophyte NEA12 mutant deleted for the entire janthitrem gene cluster, which, according to Spangenberg, also includes a itmF gene (p. 22, lines 11-12; Table 2). Although Spangenberg does not refer to the itmF gene as idtF, Spangenberg teaches the itmF gene of NEA12 encodes a prenyl transferase (p. 24, Table 2) and evidentiary reference UniProt J7FK08 teaches idtF gene encodes a prenyl transferase. As such, the itmF gene of Spangenberg is considered to be encompassed by idtF gene in instant claim 82 and an Epichloë endophyte NEA12 mutant deleted for the entire janthitrem gene cluster includes a deletion of the idtF gene.
Regarding claim 89, Spangenberg teaches the janthitrem producing endophyte is Epichloë endophyte strain NEA12 (p. 3, lines 28-31), which is an endophytic symbiont.
Regarding claim 90, for reasons stated above, in view of the combined teachings of Spangenberg, Saikia, and Scott, it would have been obvious to make an Epichloë endophyte NEA12 mutant deleted only for PP02 (idtA) and according to Spangenberg, the janthitrem gene cluster includes a itmG gene (p. 22, lines 11-12; Table 2). Although Spangenberg does not refer to the itmG gene as idtG, Spangenberg teaches the itmG gene of NEA12 encodes a geranylgeranyl diphosphate synthase (p. 24, Table 2; p. 25, lines 27-28) and evidentiary reference UniProt J7FIX8 teaches idtG gene encodes a geranylgeranyl diphosphate synthase. As such, the itmG gene of Spangenberg is considered to be encompassed by idtG gene in instant claim 90 and an Epichloë endophyte NEA12 mutant deleted only for PP02 (idtA) includes a functional idtG gene.
Therefore, the invention of claims 70-77 and 82-90 would have been obvious to one of ordinary skill in the art before the effective filing date.
Citation of Relevant Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Panaccione et al. (PNAS 98:12820-12825, 2001; cited on the attached Form PTO-892) discloses knockout of an alkaloid biosynthesis gene in a fungal endophyte in order to eliminate production of a toxic alkaloid compound (p. 12820, Abstract).
Conclusion
Status of the claims:
Claims 70-77 and 79-90 are pending in the application.
Claims 70-77 and 79-90 are rejected.
No claim is in condition for allowance.
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.
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/David Steadman/Primary Examiner, Art Unit 1656
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