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 .
Claim Status
2. The amendment, filed 12/08/25, has been entered. Claims 1-11 and 13-15 are pending. Claim 12 is cancelled. Claim 1 is amended. Claims 7-9 and 11 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 07/08/25. Claims 1-6, 10, and 13-15 are under examination.
Withdrawal of Objections/Rejections
3. The following are withdrawn from the Office Action, filed 09/11/25: none.
Maintained Rejection: Claim Rejections - 35 USC § 112
4. 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.
5. Claims 1-6, 10, and 13-15 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 Applicant is attempting to encompass with the term “conservative” in the phrase “…a conservative amino acid sequence...” in view of the subsequent phrase “…having at least 80% sequence identity…” which, by definition, encompasses sequence variants (i.e. variable, not conserved). Thus, it is unclear what is required to be “conserved”. For example, are each of the amino acid substitutions required to be conservative amino acid substitutions (e.g. leucine for isoleucine, because both are nonpolar and branched with similar chemical properties)? Or are there particular domains and/or subsequences (and if so, which ones) within the fully identified sequence (e.g. SEQ ID NO: 1) that must be conserved (i.e. not substituted) to constitute a “conserved” sequence. Accordingly, clarification is required to ascertain the metes and bounds of the claim.
Other dependent claims do not clarify the issue identified above; thus, clarification is required to remove ambiguity in the scope and thereby ascertain the metes and bounds of the claims.
Applicant’s Arguments and Response to Arguments
6. All of Applicant’s arguments have been considered but were not deemed persuasive; Accordingly, the rejection is maintained for reasons of record. For example:
With regards to the arguments that the term "conservative amino acid substitution" is defined at [0054] (see Remarks, page 5) and with regards to the link to Wikipedia for “conservative replacement” (see Remarks, page 6); the Office notes that these are not the phrases in question as the claim does not recite "conservative amino acid substitution" or “conservative replacement” but rather “a conservative amino acid sequence”. Thus, these arguments are not persuasive because they are not germane. For the sake of completeness it is also noted that paragraph [0054] does not address conservative amino acid substitution; however a discussion is in paragraph [0041].
With regards to the argument that “conservative” is known to those of ordinary skill in the biotechnology arts (see Remarks, page 5); the Office agrees as this is the basis of the rejection. However it remains the Office’s position that a conservative sequence is in conflict with 80% sequence variants, (i.e. it is one or the other, but cannot be both) as set forth previously and maintained above. Thus, this argument is not persuasive because it supports the Office’s position.
With regards to the argument that the skilled artisan would understand that a conservative sequence is one that maintains, and potentially enhances the function (see Remarks, page 6); the Office clearly disagrees. Thus, this argument is not persuasive because a conservative sequence is one that does not change (i.e. it is by definition, conserved), but “…at least 80% sequence identity…over its entire length” permits up to 20% change within that same sequence, and consequently is in direct conflict.
Therefore, all of Applicant’s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record.
Maintained Rejection: Claim Rejections - 35 USC § 112
7. 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.
8. Claims 1-6, 10, and 13-15 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.
Instant claims are drawn to a protease comprising a conservative amino acid sequence having at least 80% sequence identity with the amino acid sequence given in SEQ ID NO:1 over its entire length; wherein the protease has, in each case based on the numbering according to SEQ ID NO:1 (a) amino acid substitutions at the positions corresponding to positions 9, 130, 133, 144, 217, 224, 252, and 271; and (b) one or more further amino acid substitutions at the positions corresponding to positions 6, 89, 131, 166, 189, and 211. The protease has the asserted utility of a washing and/or cleaning agent (see specification at [0002]; and dependent claim 10).
Consequently, it is the Office’s position that (1) the claim(s) constitute(s) a "broad generic claim” based on the lack of guidance regarding sequence “variants” (i.e. which of the remaining amino acids may be substituted while maintaining the corresponding functional properties as a protease for a washing or cleaning agent; and (2) the claimed genus has substantial variation because of the numerous permutations permitted.
However, the specification does not provide adequate written description to identify the broad and variable genus of the claims because, inter alia, the specification does not disclose a correlation between the necessary structure of the polypeptide (e.g. which other amino acids must be maintained and which may be substituted in a 80% sequence variant) and the claimed function to be maintained (e.g. ability to function as a protease for a washing and/or cleaning agent). 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 the other critical amino acids or subsequences within SEQ ID NO: 1 that must be retained in order to maintain the claimed functional activity of a protease. It is noted that SEQ ID NO: 1 comprises 275 amino acids. Sequence variants that are at least 80% similar over the entire length, require 220 of the 275 to be maintained, leaving as little as 1, but up to 55, of the amino acids to be substituted (i.e. 220/275*100 = 80%; 275-220 = 55). However, as written, the claims require a minimum of 9 substitutions at particular positions (i.e. 9, 130, 133, 144, 217, 224, 252, 271; and any one of: 6, 89, 131, 166, 189, and 211) leaving up to 46 additional amino acids (i.e. 55-9 = 46) to still be modifiable while still meeting the structural limitation of at least 80% similar over the entire length. However, there are an almost unfathomable number of ways in which 1 to 46 amino acids can be selected from the 266 remaining residues (i.e. 275 total length – 9 required = 266 still available to modify) because, without any other limitations in the independent claim, each of the remaining residues can be substituted with any one of the other 19 naturally occurring amino acids and still meet the limitation (i.e. a sequence having a substitution at residue 33 with a cysteine would be structurally distinct from the sequence having a substitution at residue 33 with a serine; see MPEP 2434). Accordingly, with order of selection not important and repetition not allowed, the equation is X = 19 * [n!/(r!(n-r)!)], which results in a number having more than 50 zeros. Consequently, it is the Office’s position that 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 protease for cleaning and/or washing agents, 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 (i.e. what parts of the sequence must be retained to maintain its function as a protease), 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 SEQ ID NO 1 (i.e. wild-type protease from Bacillus pumilus DSM18097) having modifications of P9T, N130D/V, T133A, N144K, Y217M, S224A, N252T, Q271E along with S189T, S89A, and/or G131H; see Table of sequence variants on page 26 in Example 1) and exhibiting comparable or increased washing performance at 20°C/40°C by comparison with a starting variant identified as SEQ ID NO:2 (see Table of results on page 28 of Example 1). These sequence variants have 96% (i.e. maximum of 12 substitutions = 263/275*100) to 97% (i.e. minimum of 9 substitutions = 266/275*100) similarity to SEQ ID NO: 1 over its entire length. However, the specification does not adequately describe sequence variants having as little as 80% similarity over the entire length of SEQ ID NO: 1 and the claimed functional properties of the ability to function as a protease for washing and cleaning compositions, nor a nexus between the limited results for these variants and breadth and variety of sequence variants encompassed by the claims (see math above). 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 to reflect the variation within the genus (i.e. there are no species having as little as 80% similarity in sequence identity and the ability to function as a protease for a washing or cleaning agent).
Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous 80% sequence variants both the claimed structural attributes and functional properties have not yet been identified. As a reminder, MPEP 2163 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). Accordingly, it is the Office’s position that one of skill in the art would not accept the disclosure of the 4 to 5 particular sequence variants listed in the table of Example 1, all having the same 8 particular mutations, as either a sufficient number and/or variety of “representative species” for all of the billions and billions and billions of sequence variants encompassed by the broad and variable generic claims. Therefore, 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 claimed.
With regards to the state of the art, designing modified enzymes for use as a washing and/or cleaning agent was under development and thus necessarily unpredictable. For example, Vojcic et al. 2015 (Advances in protease engineering for laundry detergents; New Biotechnology 32(6):629-634; of record) teaches the identification of new proteases is an ongoing challenge including the pH dependent activity of subtilisin in general which is not completely understood (e.g. page 632, left column) and that it is extremely challenging to maintain constant level of mild bleaching (e.g. page 632, right column). Vojcic teaches subtilisins are important industrial enzymes and investigations that focus on the engineering have contrary properties requiring strong molecular interactions and flexibility in the same enzyme (e.g. see abstract and summary).
Similarly, Bryan 2000 (Protein engineering of subtilisin; Biochimica et Biophysica Acta 1543: 203-222; of record) teaches that in most protein engineering studies of subtilisin, stability is defined in terms of the loss of activity but the mechanisms of irreversible inactivation can be complex (e.g. section 2.2) and difficult to study independent of the unfolding reaction (e.g. section 2.1). Bryan teaches that although subtilisins are naturally robust as little as 1% of random amino acid substitutions will measurably change the half-time of thermal inactivation (e.g. section 2.2.4; Table 1 and references cited therein). Bryan teaches that optimizing subtilisin activity for a specific protein sequence requires evaluation of synergistic mutation effects (e.g. section 3.1).
Thus, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the polypeptide per se (e.g. which amino acid substitutions correlate to claimed functional properties of being a protease for a washing and cleaning agent) and therefore does not provide adequate written description support for which structural features of the polypeptide would predictably retain the functional activity (i.e. the state of the art is not sufficient to identify which amino acids within SEQ ID NO: 1 must be conserved in order to maintain the claimed functional properties).
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 or the specification supports the claimed invention, Applicant has not satisfied the requirements as set forth under 35 U.S.C. 112(a).
Applicant’s Arguments and Response to Arguments
9. All of Applicant’s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record. For example:
With regards to the argument that the universe of possible substitutions for the amino acids is significantly circumscribed to those that maintain activity as a protease and fall within the example conservative amino acid substitutions (see Remarks, page 6, again citing paragraph [0054]*); the Office disagrees with Applicant’s interpretation (i.e. the claims are not limited to conservative substitutions) and assessment (i.e. even if the claims were limited to conservative substitutions, the number of unique sequences encompassed is still well over billion of trillions), and again notes that there is no structure-function correlation, known or disclosed, for the other parts of the sequence that are allowed to be modified but must maintain the functional abilities of a protease. Thus, this argument is not persuasive because it is not an accurate reflection of the breadth and variability of the genus encompassed by the claims as written. *(This paragraph should have been [0041]).
With regards to the arguments pertaining to paragraph [0041], percent homology and the AlphaFold tool (see Remarks, pages 6-7); the Office notes that the claims do not require percent homology (i.e. claims are drawn to percent sequence identity which is not the same) and homology is not addressed in paragraph [0041] but rather [0028]. Thus, these arguments are not persuasive because they are not germane.
With regards to the arguments that the Office’s assertion that each residue can be substituted with any one of the other 19 naturally occurring amino acids and still meet the limitation is incorrect in the face of the claim language regarding conservative sequences and in view of the state of the field as above outlined. Applicant notes that at least two conditions must be met by any protease within the claimed language: 1) it must function as a protease; and, 2) it must contain the required substitutions. The two conditions, particularly in context of the clear language regarding substitutions and the meaning of the term, vastly constrains the world of allowable mutations (see Remarks page 7); the Office disagrees and notes that the features upon which Applicant relies are not recited in the rejected claims and maintains that, as written, the claims are not limited to conservative substitutions (yet, even if they were, the number and variety of unique sequences encompassed is still astronomical). Therefore, these arguments are not persuasive because, even though the claims are interpreted in light of the specification, limitations from the specification are not read into the claims; See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In summary, it remains the Office’s position that the independent claim, as written, is not limited to conservative substitutions either at the particular residues (i.e. see “…(a) amino acid substitutions at positions…” at line 5; and “(b) one or more further amino acid substitutions…” at line 7) or for the remaining residues that are allowed to be modified based on the “…at least 80% sequence identity…over its entire length...” limitation. In the interest of completeness, it is also noted that even if the substitutions were limited to conservative ones (which they are not), the specification would still not adequately support the breadth and variety of sequences encompassed by the limitation “…at least 80% sequence identity…over its entire length” because of the lack of structure-function correlation and/or representative species for the substitutions permitted throughout the rest of the sequence while maintaining the claimed functional properties of a protease.
Therefore, all of Applicant’s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record.
Maintained Rejection: Claim Rejections - 35 USC § 112
10. Claims 1-6, 10, and 13-15 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a protease comprising SEQ ID NO 1 with modifications of P9T, N130D/V, T133A, N144K, Y217M, S224A, N252T, Q271E along with S189T, S89A, and/or G131H; the specification does not reasonably provide enablement for sequence variants for proteases with as little as 80% similarity and the ability to function as a protease for a cleaning and/or washing agent. 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/are proteases comprising a conservative amino acid sequence having at least 80% sequence identity with the amino acid sequence given in SEQ ID NO:1 over its entire length; wherein the protease has, in each case based on the numbering according to SEQ ID NO:1, (a) amino acid substitutions at the positions corresponding to positions 9, 130, 133, 144, 217, 224, 252, and 271; and (b) one or more further amino acid substitutions at the positions corresponding to positions 6, 89, 131, 166, 189, and 211 with an asserted utility of a washing and/or cleaning agent (e.g. see specification at [0002]; and dependent claim 10). 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 (e.g. a fully described sequence with particular mutations) what other species (e.g. sequence variations thereof) may or may not work; see MPEP 2164.03.
Breadth of the claims: The broadest reasonable interpretation of the claims covers an almost unfathomable number partial structures (i.e. more than a billion trillion unique sequence variants; see math above) claimed only by a functional property. However, without guidance on which of the structural components are required (i.e. which of the remaining amino acids must be conserved) to maintain their claimed functions (i.e. a protease capable of functioning as a washing and cleaning agent) and without a disclosed correlation between function and structure, undue experimentation would be required to determine which of the numerous options 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.
Amount of direction provided by Inventor and Existence of Working Examples: The specification provides complete structural information for SEQ ID NO 1 (i.e. wild-type protease from Bacillus pumilus DSM18097) having modifications of P9T, N130D/V, T133A, N144K, Y217M, S224A, N252T, Q271E along with S189T, S89A, and/or G131H; see Table of variants on page 26 in Example 1) and exhibiting comparable or increased washing performance at 20°C/40°C by comparison with a starting variant identified as SEQ ID NO: 2 (see Table of results on page 28 of Example 1). These sequence variants have 96% (i.e. 12 substitutions = 263/275*100) to 97% (i.e. 9 substitutions = 266/275*100) similarity to SEQ ID NO: 1 over its entire length. The specification does not sufficiently disclose any sequence variants having as little as 80% similarity and the claimed functional properties, nor a nexus between the limited results presented and the full scope encompassed by the claims. Accordingly, the scope of the claims is extremely broad compared to the guidance and exemplification provided in the specification. Therefore, the only way to determine if the functional property of a sequence variant is indeed retained, is empirical testing of each variant encompassed. Consequently, based on the almost unfathomable number of possibilities of those variants, 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, designing modified enzymes for use as a washing and cleaning agent was under development and thus necessarily unpredictable. For example, Vojcic et al. 2015 (Advances in protease engineering for laundry detergents; New Biotechnology 32(6):629-634) teaches the identification of new proteases is an ongoing challenge including the pH dependent activity of subtilisin in general is not completely understood (e.g. page 632, left column) and that it is extremely challenging to maintain constant level of mild bleaching (e.g. page 632, right column). Vojcic teaches subtilisins are important industrial enzymes and investigations that focus on the engineering have contrary properties requiring strong molecular interactions and flexibility in the same enzyme (e.g. see abstract and summary). Similarly, Bryan 2000 (Protein engineering of subtilisin; Biochimica et Biophysica Acta 1543: 203-222) teaches that in most protein engineering studies of subtilisin, stability is defined in terms of the loss of activity but the mechanisms of irreversible inactivation can be complex (e.g. section 2.2) and difficult to study independent of the unfolding reaction (e.g. section 2.1). Bryan teaches that although subtilisins are naturally robust as little as 1% of random amino acid substitutions will measurably change the half-time of thermal inactivation (e.g. section 2.2.4; Table 1 and references cited therein). Bryan teaches that optimizing subtilisin activity for a specific protein sequence requires evaluation of synergistic mutation effects (e.g. section 3.1). Therefore, because the claimed functions cannot be predicted from the claimed partial structures, 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 sequence variations encompassed.
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 4-5 variants all having the same specific mutations (i.e. P9T, N130D/V, T133A, N144K, Y217M, S224A, N252T, Q271E) along with one of more of S189T, S89A, and G131H mutations, to all of the other sequence variants with the same functional properties, as broadly as is claimed. The skilled artisan simply cannot envision the structures required (i.e. what 80% must be conserved while maintaining the functional properties), 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 sequence variations (i.e. ones with as little as 80% sequence identity) would 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 (i.e. well-defined sequences having 9-12 particular substitutions) 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 sequence variants, 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. determining if a particular 80% sequence variant does indeed retain protease and/or washing and cleaning properties), would not reduce the amount of experimentation required because the functional properties still must be determined empirically. 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. 80% sequence variations) claimed only by their functional properties, 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. Accordingly, Applicant has not satisfied the requirements as set forth under 35 U.S.C. 112(a).
Applicant’s Arguments and Response to Arguments
11. All of Applicant’s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record. For example:
With regards to the argument that the definition of "conservative" both as contextualized in the Specification and as commonly used in the art, and in view of the required mutations present, Applicant believes that, contrary to the assertion of the Office the universe of potential proteases fitting the claims is naturally bounded and constrained (see Remarks, page 7); the Office disagrees and notes “a conservative amino acid sequence” is not defined in the specification and the claims are not limited to “conservative amino acid substitutions” and again points to the language in the independent claim: “…(a) amino acid substitutions at positions…” at line 5; and “(b) one or more further amino acid substitutions…” at line 7, neither of which requires or otherwise limits the substitutions to be conservative. Further, the Office disagrees with Applicant’s limited interpretation and notes that there are more than 1 x 1052 (i.e. 1 followed by 52 zeros) of unique sequences encompassed by the limitation “…at least 80% sequence identity…over its entire length...” because there are that many ways to select 42 amino acids (“r” in the equation) from the remaining 266 amino acids (“n” in the equation) within SEQ ID NO: 1. And this number does not account any sequences having less than 42 additional substitutions (e.g. does not account for those having only 2, 8, 14, etc. additional substitutions) and does not account for sequence variations having different amino acid substitutions at the same residue (i.e. does not account for the structural differences between, for example, T33S, T33A, and T33V, which are conservative substitutions, with those of T33C and T33M, which are non-conservative substitutions). Therefore, these arguments are not persuasive because the actual number of sequence variants encompassed by the claims, as written, is even larger than 1 x 1052 which even the ordinary artisan would recognize as massive.
With regards to the argument that the Office factually errs in the assertion that the substitution of any natural amino acid is acceptable (see Remarks, page 7-8); the Office disagrees and again notes “a conservative amino acid sequence” is not defined in the specification and the claims are not limited to “conservative amino acid substitutions” and again points to the language in the independent claim: “…(a) amino acid substitutions at positions…” at line 5; and “(b) one or more further amino acid substitutions…” at line 7, as set forth above. Thus, this argument is not persuasive because it is not accurate as the Office did not factually err with its interpretation.
Therefore, all of Applicant’s arguments have been considered but were not deemed persuasive; accordingly, the rejection is maintained for reasons of record.
Conclusion
12. No claims are allowed.
13. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/MARY MAILLE LYONS/Examiner, Art Unit 1645
January 12, 2026