DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
2. The information disclosure statement (IDS) submitted on 02/17/25 was filed and entered. The submission is in compliance with the provisions of 37 CFR 1.97 and has been considered by the Examiner.
3. The listing of references in the specification is not a proper information disclosure statement (IDS) because 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office; and MPEP § 609.04(a) states "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the Examiner on form PTO-892, or by Applicant on an IDS, they have not been considered.
Election/Restrictions
4. Applicant's election with traverse of Group I, and Trichoderma, SEQ ID NO: 1 and VHH, in the reply filed on 12/19/25, is acknowledged.
The traversal is on the ground(s) that although Yuanchao describes decreased expression of two proteases (Apw1 and Apw2) in Tricoderma, Yuanchao is completely silent on increased production or improved stability of a compound of interest. Additionally, the Arel deletion drastically decreases expression of the major cellulase proteins Cbh1 and Cbh2 which reduces the industrial applicability of this modified Trichoderma strain as Cbh1 and Cbh2 promoters are very often used to drive expression of a heterologous protein to high levels. This is in stark contrast to the microbial host cells according to the present invention which are not only able to improve VHH proteins as produced therein but also are capable of doing so in a system using the Cbh1 and Cbh2 promoters (see Remarks, page 9).
This is not found persuasive because it is not commensurate in scope with the independent claims, as written. For example, as set forth in the Restriction Requirement, some of groups do not even share a technical feature and therefore cannot have unity of invention. For those groups that do, the shared technical feature is only a modified microbial host cell, wherein the modification affects production, stability or function of as little as one polypeptide (e.g. see independent claim 11, which does not require increased production of a compound of interest or the expression of the major cellulase proteins Cbh1 and Cbh2). However, this shared technical feature is not deemed a special technical feature (i.e. required for unity of invention) because it does not make a contribution over the art since, for example, Yuanchao Qian (see Restriction) teaches modified microbial cells wherein the modification affected, inter alia, the production of the corresponding protein (e.g. see decreased expression of protease Apw1) as conceded by Applicant above.
Therefore, the requirement is still deemed proper and is therefore made FINAL.
Claim Status
5. The amendment, filed 12/19/25, has been entered.
6. Claims 1-23 are pending. Claim 23 is newly added. Claims 11-14, 16-17, 19-20, 22 and 23 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/19/25. Claims 1-10, 15, 18, and 21 are under examination.
Claim Objections
7. Claim 4 is objected to because of the following informalities: missing words and punctuation. Claim 4 includes consecutive commas with a gap where a genus is expected (see line 5) and missing commas between the genera (e.g. Thielavia and Chrysosporium; line 4). Appropriate correction throughout the entire list is required.
Improper Markush Grouping Rejection
8. Claims 1, 8, 9, and 10 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use (emphasis added). A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature; See MPEP § 706.03(y).
The Markush grouping(s) of (A) SEQ ID NO: 1, 28, 33, 36, 58 and 59 in claim 1 and each of SEQ ID NOs (B) [45, 49, 53]; (C) [46, 50, 54]; and (D) [47, 51, 55] in claims 8 and 9; and (E) SEQ ID NO: 43, 44, 48, 52, 56, and 57 in claim 10 is/are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use as evidenced by the distinct sequences of amino acids having between zero (see CDRs) to less than 37% similarity (e.g. see Table on page 5 of specification). Therefore, the sequences within each identified set of sequences (A)-(E) above, do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims (although, note that the restriction requirement still holds) and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 101 and/or 35 USC § 112
9. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
10. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
11. Claims 15 and 21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter; and/or, in the alternative, 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.
Claims 15 and 21 are improperly written as “Use of…” claims.
With regards to 101, the claims are not proper process claims and thus do not fall within at least one of the four categories of patent eligible subject matter since the courts have deemed claiming a process without setting forth any steps involved in the process is improper; see MPEP 2173.05(q).
With regards to 112(b), the claims are indefinite because the claims lack positively recited steps delimiting how this use is actually practiced; see MPEP 2173.05(q).
For the purposes of compact prosecution, it is noted that claims 15 and 21 have been interpreted as drawn to a product and the intended use thereof. Nevertheless, clarification is required to ascertain the metes and bounds of these claims.
Claim Rejections - 35 USC § 112
12. Claims 1-10 and 18 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.
Claim 1 is indefinite because it is unclear what is required based on the elements listed as (a) a modification that affects at least one polypeptide; and (b) a modulation in protease (i.e. a polypeptide) activity (in other words, if the polypeptide in (a) were a protease, then can both (a) and (b) be satisfied with as little as one modification?); and coupled to a second list using the same notation (a), (b), (c) or (d) indented under the first (b) but which appears to refer to the first (a). Thus, it is unclear how many modifications are required, and why the second list uses the same notation as the first list; and/or if the second list applies to the first (b) under which it is located or to the first (a) to which it appears to refer. If (b), then it is also unclear how options (a)-(d) relate to modulation in protease activity if these sequences do not correspond to protease as the polypeptide to be affected. Furthermore, the second (b) is drawn to a genomic nucleotide sequence (i.e. a sequence of nucleotides) but must comprise a polypeptide sequence (i.e. a sequence of amino acids) between 80 and 98% identical to a particular SEQ ID NO, which is not possible, thus clarification as to what is required is also necessary (i.e. is it the polynucleotide or a polypeptide?). In addition, in the first (a) it is the microbial host cell that has be modified (see line 2) and the modification has to affect the polypeptide but the polypeptide does not appear to require modification per se; however in line 22, it appears that the particular polypeptide must be modified (i.e. not the host cell per se) which further introduces ambiguity as to what are the required structural elements of the microbial host cell. Consequently, clarification is required to remove scope ambiguity and thereby ascertain the metes and bounds of the claim.
Claim 1 and 3 are indefinite because it is unclear if Applicant intended to require the comparison with a parental strain, since both claims include the conditional phrase “… if compared with”. In the interest of compact prosecution, it is noted that these limitations are met if no comparison is made, since the comparison is claimed as optional. Nevertheless, clarification is required to ascertain the metes and bounds of the claim. The Office recommends, for example, “…has at least about 40% less protease activity [[if]] as compared with the …” if indeed the comparison is desired.
Regarding claim 4, the phrases “for example” (see line 2) and "preferably" (see line 5) render the claim indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention; See MPEP § 2173.05(d). The terms introduce ambiguity of scope because it is unclear if the claim was intended to be limited to the specific “preferred” embodiment, or if the claim encompasses the broader grouping identified. A broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired and raises a question or doubt as to whether the feature introduced by the narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims; See MPEP § 2173.05(c). Thus, clarification is required to ascertain the metes and bounds of the claim.
Regarding claim 6, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired; See MPEP § 2173.05(c). In the present instance, claim 6 recites the broad recitation an antibody, and the claim also recites a heavy chain antibody or a functional fragment thereof, a single domain antibody, a heavy chain variable domain of an antibody or a functional fragment thereof, a heavy chain variable domain of a heavy chain antibody or a functional fragment thereof (VHH), a variable domain of camelid heavy chain antibody or a functional fragment thereof, a variable domain of a new antigen receptor (vNAR), a variable domain of shark new antigen receptor or a functional fragment thereof, a minibody, a nanobody, a nanoantibody, or an engineered CH2 domain which are each narrower statements of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Other dependent claims do not clarify the issues identified above. Thus, clarification is required.
Claim Rejections - 35 USC § 112
13. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
14. Claims 1-10, 15, 18, and 21 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 is a written description rejection.
Instant claims are drawn to a microbial host cell which is characterized by: (a) having been modified and where this modification affects the production, stability and/or function of at least one polypeptide; and (b) having a modulation in protease activity if compared with a parent microbial host cell which has not been modified and measured under the same conditions wherein the at least one polypeptide: (a) comprises a sequence of SEQ ID NOs: 1 (see sequence election) or a polypeptide at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% identical thereto, or an ortholog thereof; wherein the at least one polypeptide is a promoter of transcription and has been modified to reduce its production, stability and/or function, and the modulation in protease activity is a reduction or deficiency in protease activity, and wherein the microbial host cell further comprises at least one polynucleotide coding for a compound of interest.
Consequently, it is the Office’s position that (1) the claim(s) constitute(s) a "broad generic claim” based on (1A) generically claimed microbial host cells; and “modifications” thereof; and “modulations in protease activity” and “compounds of interest”; and (1B) the lack of guidance regarding sequence “variants” and (2) the claimed genus has substantial variation because of the numerous options, combinations, and permutations permitted.
However, with regards to the sequence variants, the specification does not provide adequate written description to identify the broad genus of the claims because, inter alia, the specification does not disclose a correlation between the necessary structure of the polypeptide (e.g. which 2 to 20% of the amino acids in the polypeptide may be substituted within a claimed sequence or ortholog thereof); and the claimed function to be maintained (e.g. promotor of transcription modified to reduce production, stability and/or function). It is noted that while the description of the ability of a claimed protein sequence may generically describe that protein molecule's function, it does not describe the molecule itself. For example, the specification fails to identify critical amino acids or subsequences within SEQ ID NO: 1 that must be retained in order to maintain the claimed functional activity. Consequently, the specification fails to describe the common attributes or structural characteristics that identify the members of this genus and because the genus of sequences is highly variable (i.e. each sequence has a unique structure; see MPEP 2434), the characteristics of the ability to function as a promotor of transcription, is insufficient to describe the genus. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a massive number of partial structures claimed only by a functional characteristic because, without an art-recognized structure-function correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. Thus, disclosure of function alone is little more than a wish for possession and it does not satisfy the written description requirement; See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate").
Further, MPEP §2163 states that if a biomolecule is described only by a functional characteristic (as in the instant case), without any disclosed correlation between function and structure of the sequence (as in the instant case), it is not sufficient for written description purposes, even when accompanied by a method of obtaining the claimed sequences. MPEP §2163 does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number to adequately describe a broad genus. For example, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus (e.g. see In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618). Furthermore, the disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
In the instant case, the specification provides complete structural information for elected SEQ ID NO: 1. However, the claims, as written, also encompass partial structures of SEQ ID NO: 1. In addition, Applicant defined “about” to encompass +/- 10% (see page 6, line 41) so these claimed variants (i.e. 80-98%) encompass partial structures with as little as 70% similarity based on the “about”. However, it is the Office's position that the polypeptide sequence variants have not been described with sufficient particularity, such that one skilled in the art would recognize that Applicant had possession of the claimed invention, at the time of filing, because of (A) a lack of a correlation, known or disclosed, between the claimed functional requirements and the structures that meet those requirements (see above); and/or (B) a lack of a representative number and variety of species to constitute possession of the full scope of the claimed genus.
With regards to the other limitations (i.e. haphazard combinations of generically claimed microbial host cells; “modifications” thereof; “modulations in protease activity” and/or “compounds of interest”; it is noted that the specification describes genetically modified Trichoderma reesei host cells (i.e. one example of a particular host cell) having its Are1 gene (i.e. one example of one modified polypeptide) deleted (see Example 2) and having the ability for recombinant expression of a VHH-1 protein sequence (i.e. one compound of interest; see Examples 3, 7 and Figure 10A). The specification does not adequately describe a nexus between these limited results and other microbial hosts (i.e. encompasses all bacteria, all microscopic fungi, all protists, all microscopic helminths and arthropods, etc.). It is noted that Example 12 appears to provide support for one additional fungal host cell (i.e. Myceliophthora heterothallica), but there are no corresponding results to support that this modified microbe was similarly capable of heterologous protein expression for a compound of interest, but rather only that the AreA gene could also be deleted (e.g. see Example 13). Further, the specification does not adequately describe modified host cells selected from the genera Aspergillus, Acremonium, Thielavia, Chrysosporium, Penicillium, Talaromyces, Rasamsonia, or Fusarium or of the species Aspergillus niger, A. nidulans, Aspergillus awamori, Aspergillus foetidus, Aspergillus sojae, Aspergillus fumigatus, Aspergillus oryzae, Acremonium alabamense, Myceliophthora thermophila, Myceliophthora heterothallica, Thermothelomyces heterothallica, Thermothelomyces thermophilus, Thielavia terrestris, Chrysosporium lucknowense, Fusarium oxysporum, Rasamsonia emersonii, Talaromyces emersonii, Penicillium chrysogenum, Penicillium oxalicum or Neurospora crassa. Furthermore, the specification does not adequately describe a nexus between the limited results and other polypeptides to be generically “modified” or “modulated” such that compounds of interest including, but not limited to, heterologous proteins could be expressed. The specification does not adequately describe a nexus between these limited results and other compounds of interest (i.e. not limited to proteins). The specification does not adequately describe the production of antibodies having mixed and matched CDRs (see claim 8) other than those found as arranged in claims 9 and 10. The specification does not adequately describe the expression of sequences found in claims 9 and 10 in any microbial host except for their modified Trichoderma reesei.
Accordingly, the specification also does not provide adequate written description to identify the broad and variable genus of the claims because, inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species (i.e. examples) to reflect the variation within the genus (e.g. mixed-and-matched combinations of any and all microbial host cells, with generic modifications for any and all polypeptides, and generic modulations of protease activity, and/or any and all compounds of interest using poorly described sequence variants and/or orthologs thereof). Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous options, combinations and permutations having the claimed structural attributes and functional properties have not yet been identified. MPEP 2163 which states an adequate written description of a chemical invention 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; see, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004). Therefore, it is the Office’s position that even one of skill in the art would not accept the disclosure of one modified Trichoderma reesei host cell (i.e. one example of a particular filamentous fungal host cell) having its Are1 gene deleted (i.e. one example of one modified polypeptide via the modification of its corresponding gene) and having the ability to recombinantly express a heterologous protein (i.e. one example using a VHH sequence) as either a sufficient number and/or variety of “representative species” for all of options, combinations and permutations encompassed by the broad and variable claims, as written. Consequently, it is the Office’s position that one of skill in the art would not conclude that Applicant was in possession of the entire genus.
With regards to the state of the art, modifying fungal host cells for the production and expression of heterologous proteins was under development and thus necessarily unpredictable. For example, Nevalaine et al. 2014 (Making recombinant proteins in filamentous fungi – are we expecting too much? Frontiers in Microbiology V5(75):1-10) teaches genetically modified hosts cells used for the production of recombinant proteins are typically high-protein secreting mutant strains that have been selected for a specific purpose, such as efficient production of cellulose-degrading enzymes; but that somewhat surprisingly, sequencing of the genomes of fungal host cells such as Trichoderma reesei, widely used as an expression host for recombinant gene products, shed very little light on the nature of changes that boost high-level protein secretion and that attempts to increase yields of heterologous proteins in fungal hosts have resulted in variable success (e.g. see abstract). Nevalaine teaches it is evident that identifying individual genes and changes in the genomes will not provide an answer to the pending question of secretion supremacy; but more likely, the answer will hide in complex interactions between relevant genes and proteins and their regulation (i.e. no recognized, structure-functional correlations in the art; emphasis added).
Similarly, Qian 2019 (The GATA-Type Transcriptional Factor Are1 Modulates the Expression of Extracellular Proteases and Cellulases in Trichoderma reesei; International Journal of Molecular Science; of record) teaches the expression levels of the major cellulase transcription activator Xyrl and the repressor Crel had no significant difference between Trichoderma reesei Dare1 mutants (i.e. genetically modified host cells) and the corresponding parental strain (i.e. modification does not predictably lead to observed differences), indicating that the regulatory mechanism deserves further investigation as it is not fully understood (i.e. under development; see abstract, introduction, section 2.5). Qian teaches the function of Are1 mutations needs to be confirmed experimentally (i.e. not predictable; e.g. see page 9, section 3).
Thus, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the microbial host cell, genetic modifications, sequence variants and/or compounds of interest to be produced and therefore does not provide adequate written description support for which structural features would predictably retain their functional activities.
Consequently, neither the specification nor the state of the art provides sufficient written description to support the genus encompassed by the claims. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.). Given the above analysis of the factors as a whole, which the courts have determined are critical in determining whether Applicant is in possession of the claimed invention, Applicant has not satisfied the requirements as set forth under 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 112
15. Claims 1-10, 15, 18, and 21 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for genetically modified Trichoderma reesei host cells having the Are1 gene (i.e. SEQ ID NO: 1) deleted and having the ability for recombinant expression of a heterologous VHH protein; the specification does not reasonably provide enablement for all microbial host cells having any and all modified polypeptides (including sequence variants of SEQ ID NO: 1), combined with all proteases to modulate, and/or all compounds of interest to produce. 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. This is a scope of enablement rejection.
Factors to be considered in determining whether undue experimentation is required, are set forth in In re Wands, 8 USPQ2d 1400. They include (1) the quantity of experimentation necessary, (2) the amount of 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. Although all the factors were considered, the most relevant ones are discussed below. In the instant case:
Nature of the invention: The nature of the invention is microbial host cell characterized by: (a) having been modified and where this modification affects the production, stability and/or function of at least one polypeptide; and (b) having a modulation in protease activity wherein the at least one polypeptide: (a) comprises a sequence of SEQ ID NOs: 1 (see sequence election) or a polypeptide at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% identical thereto, or an ortholog thereof; wherein the at least one polypeptide is a promoter of transcription and has been modified to reduce its production, stability and/or function, and the modulation in protease activity is a reduction or deficiency in protease activity, and wherein the microbial host cell further comprises at least one polynucleotide coding for a compound of interest. Therefore, the nature of the invention is a chemical case, where there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; see MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to practice the full scope of the claimed invention, with a reasonable expectation of success, because it would not be predictable from the disclosure of one particular species (only one fully described example) what other species (other microbial host cells in combination with other polypeptides to be modified, proteases to be modulated and compounds of interest to be produced) may or may not work; MPEP 2164.03.
Breadth of the claims: The broadest reasonable interpretation of the claims covers numerous partial structures (i.e. 70-98% sequence variations) used in haphazard combinations with an astronomical number and variety of microbial hosts, polypeptides to modify, proteases to modulate, and/or compounds of interest to produce. For example, microbial hosts encompass all bacteria, all eukaryotic protists and parasites, all microscopic arthropods and/or helminths along with all microscopic fungi including members of Aspergillus, Acremonium, Thielavia, Chrysosporium, Penicillium, Talaromyces, Rasamsonia, and Fusarium, in general; and the species Aspergillus niger, A. nidulans, Aspergillus awamori, Aspergillus foetidus, Aspergillus sojae, Aspergillus fumigatus, Aspergillus oryzae, Acremonium alabamense, Myceliophthora thermophila, Myceliophthora heterothallica, Thermothelomyces heterothallica, Thermothelomyces thermophilus, Thielavia terrestris, Chrysosporium lucknowense, Fusarium oxysporum, Rasamsonia emersonii, Talaromyces emersonii, Penicillium chrysogenum, Penicillium oxalicum and Neurospora crassa, in particular. However, without guidance on which of the structural components are required (i.e. which amino acids must be conserved in a sequence variant; which microbial hosts; which polypeptides to modify; which proteases to modulate) to maintain their claimed functions (i.e. produce which compounds of interest) and without a disclosed correlation between function and structure, undue experimentation would be require to determine which of the numerous options, combinations, and permutations actually work. Accordingly, undue experimentation would be required to practice the full scope of the claimed invention, with a reasonable expectation of success, because while enablement is not precluded by the necessity for routine screening, if a large amount of screening is required, the specification must provide a reasonable amount of guidance with respect to the direction in which the experimentation should proceed and such guidance has not been provided in the instant specification (see below).
Amount of direction provided by Inventor and Existence of Working Examples: The specification discloses genetically modified Trichoderma reesei host cells (i.e. one example of a particular host cell) having its Are1 gene (i.e. one example of one modified polypeptide) deleted (see Example 2) and having the ability for recombinant expression of a protein (i.e. one compound of interest, VHH-1; see Examples 3, 7 and Figure 10A). The specification does not sufficiently disclose a nexus between these limited results and other microbial hosts (i.e. encompasses all bacteria, all microscopic fungi, all protists, all microscopic helminths, etc.). It is noted that Example 12 appears to provide support for one additional fungal host cell (i.e. Myceliophthora heterothallica), but there are no corresponding results to support that this modified microbe was similarly capable of heterologous protein expression for a compound of interest, but rather only that the AreA gene could also be deleted (e.g. see Example 13). The specification does not sufficiently disclose modified host cells selected from the genera Aspergillus, Acremonium, Thielavia, Chrysosporium, Penicillium, Talaromyces, Rasamsonia, or Fusarium or of the species Aspergillus niger, A. nidulans, Aspergillus awamori, Aspergillus foetidus, Aspergillus sojae, Aspergillus fumigatus, Aspergillus oryzae, Acremonium alabamense, Myceliophthora thermophila, Myceliophthora heterothallica, Thermothelomyces heterothallica, Thermothelomyces thermophilus, Thielavia terrestris, Chrysosporium lucknowense, Fusarium oxysporum, Rasamsonia emersonii, Talaromyces emersonii, Penicillium chrysogenum, Penicillium oxalicum or Neurospora crassa. Further, the specification does not sufficiently disclose a nexus between the limited results and other polypeptides to be generically “modified” or “modulated” such that compounds of interest including heterologous proteins could be expressed. The specification does not sufficiently disclose a nexus between these limited results and other compounds of interest (i.e. not limited to proteins). The specification does not sufficiently disclose the production of antibodies having mixed and matched CDRs (see claim 8) other than those found as arranged in claims 9 and 10. The specification does not sufficiently disclose the expression of sequences found in claims 9 and 10 in any microbial host except for their modified Trichoderma reesei. With regards to the sequences in claim 1, the specification provides complete structural information for elected SEQ ID NO: 1. However, the claims, as written, also encompass partial structures of SEQ ID NO: 1 (including defining “about” to encompass +/- 10%, see page 6, line 41, so the claimed variants (i.e. 80-98%) encompass as little as 70% similarity based on the “about”). The specification does not sufficiently disclose sequence variants meeting these structural limitations while maintaining their claimed functional attributes.
Accordingly, the scope of the claims is extremely broad compared to the guidance and exemplification provided in the specification and the only way to determine if the functional property (i.e. the ability to produce a compound of interest) of any given combination is indeed retained, is empirical testing of each and every variant encompassed. Consequently, based on the almost unfathomable number of possibilities, a non-routine amount of experimentation would be required to practice the full scope of the invention, with a reasonable expectation of success, because testing such a vast number of options would be easily recognized by the skilled practitioner to be disproportionately demanding and thus rise to the level of non-routine.
State of the Prior Art and Level of Predictability in the Art: With regards to the state of the art, modifying fungal host cells for the production of heterologous expressed proteins was under development and thus necessarily unpredictable. For example, Nevalaine et al. 2014 (Making recombinant proteins in filamentous fungi – are we expecting too much? Frontiers in Microbiology V5(75):1-10) teaches genetically modified hosts cells used for the production of recombinant proteins are typically high-protein secreting mutant strains that have been selected for a specific purpose, such as efficient production of cellulose-degrading enzymes; but that somewhat surprisingly, sequencing of the genomes of fungal host cells such as Trichoderma reesei, widely used as an expression host for recombinant gene products, shed very little light on the nature of changes that boost high-level protein secretion and that attempts to increase yields of heterologous proteins in fungal hosts has resulted in variable success (e.g. see abstract). Nevalaine teaches it is evident that identifying individual genes and changes in the genomes will not provide an answer to the pending question of secretion supremacy; but more likely, the answer will hide in complex interactions between relevant genes and proteins and their regulation (i.e. no recognized, structure-functional correlations in the art).
Similarly, Qian 2019 (The GATA-Type Transcriptional Factor Are1 Modulates the Expression of Extracellular Proteases and Cellulases in Trichoderma reesei; International Journal of Molecular Science; of record) teaches the expression levels of the major cellulase transcription activator Xyrl and the repressor Crel had no significant difference between Trichoderma reesei Dare1 mutants (i.e. genetically modified host cells) and the corresponding parental strain (i.e. modification does not predictably lead to observed differences), indicating that the regulatory mechanism deserves further investigation as it is not fully understood (i.e. under development; see abstract, introduction, section 2.5). Qian teaches the function of Are1 mutations needs to be confirmed experimentally (i.e. not predictable; e.g. see page 9, section 3).
Thus, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the microbial host cell, genetic modifications, sequence variants and/or compounds of interest to be produced. Therefore, because the claimed functions cannot be predicted from the claimed partial structures or variations thereof, the functional characteristics must be determined empirically. Consequently, the full scope of the claims is not enabled because even the skilled artisan cannot make and use the invention, with a reasonable expectation of success, without an undue amount of experimentation, based on the astronomically vast number of options, combinations, and permutations permitted.
Relative Skill of Those in the Art: The relative level of skill of those in the art is deemed to be high (e.g. PhD level); however, even one of skill in the art could not predictably extrapolate the teachings in the specification, limited to genetically modified Trichoderma reesei host cells having the Are1 gene (i.e. SEQ ID NO: 1) deleted and having the ability for recombinant expression of a heterologous VHH protein, to any and/or all other microbial host cells having any and all modified polypeptides (e.g. sequence variants of SEQ ID NO: 1), combined with all proteases to modulate, and/or compounds of interest to produce. The skilled artisan simply cannot envision the structures and combinations required, thus conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method used to determine such structures or to test for such properties, after the fact. Thus, even one of skill in the art, would have to engage in undue experimentation to determine which options, combinations and permutations retain the necessary functional properties and thereby carry out the full scope of the invention as claimed.
Quantity of Experimentation Necessary Based on Content of the Disclosure: The specification does not enable the genus because where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. This is because it is not obvious from the disclosure of one particular species, what other species will work; see MPEP 2164.03. One of skill in the art would neither expect nor predict the appropriate functioning of the numerous variants alone or in haphazard combinations with generically claimed microbial hosts, polypeptides to modify, proteases to modulate, and/or compounds of interest to produce, and accordingly, without such guidance, the experimentation left to those skilled in the art is unnecessarily and improperly extensive and undue. It is noted that providing methods for determining the functional properties (i.e. checking to determine if a particular combination works), would not reduce the amount of experimentation required because the functional properties still must be determined empirically (i.e. after the fact). Therefore, the scope of enablement provided to one skilled in the art is not commensurate with the scope of protection sought by the claims.
Therefore, in view of the lack of guidance and direction provided by Applicant there would be undue experimentation required to practice the claimed partial structures (e.g. sequence variations in haphazard combinations with generically claimed microbial hosts, polypeptides to modify, proteases to modulate, and/or compounds of interest to produce), with a reasonable expectation of success, absent a specific and detailed description in Applicant's specification of how to effectively make and/or use the full scope of the claimed invention.
Thus, Applicant has not satisfied the requirements as set forth under 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 102
16. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
17. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
18. Claims 1-5, 15 and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Qian 2019 (The GATA-Type Transcriptional Factor Are1 Modulates the Expression of Extracellular Proteases and Cellulases in Trichoderma reesei; International Journal of Molecular Science).
Qian teaches compositions comprising genetically modified Trichoderma reesei, including Dare1 mutants (i.e. a microbial host cell characterized by having been modified) derived from parental strains (identified as strain QM9414) wherein under some circumstances some protease activity was abolished (i.e. modulation of protease activity; a reduction or deficiency in protease activity) but transcription of apw1 (a gene encoding a compound of interest) was increased in the presence of ammonium and transcription of cbh1, cbh2, egl1 and egl2 (i.e. also genes encoding compounds of interest) was increased in the presence of peptone (e.g. page 9, sections 2.5 and 3; and figure 6; meeting limitations found in instant claims 1, 2, 4, and 5).
With regards to claim 3 (and similarly in claim 1), and the limitation “…wherein the microbial host cell or a fermentation broth or cell culture medium containing said modified microbial host cell has at least about 40% less protease activity if compared with the intracellular environment of the parent microbial host cell which has not been modified or a fermentation broth or cell culture medium containing said parent microbial host cell which has not been modified and measured under the same conditions” (emphasis added); the limitation does not appear to add a positively recited component to the microbial host cell (i.e. a product) and has thus been interpreted as a functional property of the claimed structures (see MPEP 2112.01) and/or the intended use of the claimed product (see MPEP 2144.07). Further, the claim limitation is written in the conditional (see “if compared with”) thus, whenever a comparison is not made, then the limitation also appears to have been met.
With regards to claims 15 and 21, these limitations have been interpreted as the intended use of the claimed product; see MPEP 2144.07.
Therefore, Qian anticipates the invention as claimed.
Claim Rejections - 35 USC § 102
19. Claims 1-7, 15, 18, and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Landowski et al. 2017 (WO 2017/025586; of record – see IDS).
Landowski teaches compositions comprising genetically modified Trichoderma reesei cells having mutations in one or more genes encoding protease enzymes resulting in a reduced activity in the one or more proteases along with polynucleotides encoding one or more heterologous polypeptides, including antibodies (e.g. see [0006-0014]; meeting limitations found in instant claims 1, 2, 4, 5, 6, 15 and 21). Landowski teaches the modifications include modifications to the activating domains of transcription factors (e.g. [0034-0036]; also meeting limitations found in instant claim 1). Landowski teaches polypeptides of interest include antibody and antibody fragments including the heavy chains (e.g. [0078-79]; meeting limitations found in instant claims 7, 18 and 21). Landowski teaches multiple transcription regulators (e.g. see Tables 3 and 4) meeting the broadest reasonable interpretation of an ortholog of the claimed polypeptide in claim 1 because they perform the same function (i.e. promoter of transcription).
With regards to claim 3 (and similarly in claim 1), and the limitation “…wherein the microbial host cell or a fermentation broth or cell culture medium containing said modified microbial host cell has at least about 40% less protease activity if compared with the intracellular environment of the parent microbial host cell which has not been modified or a fermentation broth or cell culture medium containing said parent microbial host cell which has not been modified and measured under the same conditions” (emphasis added); the limitation does not appear to add a positively recited component to the microbial host cell (i.e. a product) and has thus been interpreted as a functional property of the claimed structures (see MPEP 2112.01) and/or the intended use of the claimed product (see MPEP 2144.07). Further, the claim limitation is written in the conditional (see “if compared with”) thus, whenever a comparison is not made, then the limitation also appears to have been met.
With regards to claims 15 and 21, these limitations have been interpreted as the intended use of the claimed product; see MPEP 2144.07.
Accordingly, Landowski anticipates the invention, as claimed.
Pertinent Art
20. The following prior art, made of record and not relied upon, is considered pertinent to applicant’s disclosure. Beloglazova et al. 2024 (US 12,098,378). For the sake of compact prosecution, it is noted that SEQ ID NO: 43, 44, 48, 52, 56 and 57 having CDRS having SEQ ID NO: 45, 46, 47; or SEQ ID NO: 49, 50, 51; or SEQ ID NO: 53, 54, 55 as found in dependent claims 8, 9 and 10 are not free of the art because 100% sequence identity matches can be found in US 12,098,378. However, it is also noted that this reference has a common assignee (i.e. Biotalys) with the instant application, but a different inventive entity (e.g. different inventors). Thus, based upon the earlier effectively filed date of the reference, Beloglazova et al. 2024 (priority to 03/31/20) would constitute prior art under 35 U.S.C. 102(a)(2). Although Beloglazova teaches expression of these polypeptides in host cells (in general), they do not teach expression in Trichoderma reesei, in particular.
Conclusion
21. No claims are allowed at this time.
22. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY MAILLE LYONS whose telephone number is (571)272-2966. The examiner can normally be reached on Monday-Friday 8 am to 5 pm EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http: //www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Dan Kolker can be reached on (571)-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARY MAILLE LYONS/Examiner, Art Unit 1645
February 3, 2026