DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s submission filed on April 2, 2026 has been entered and considered. Rejections and/or objections not reiterated from the previous action mailed November 4, 2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Status of the Claims
Claims 1 and 7 have been amended to more precisely define the claimed the nucleic acid molecule encoding a Squalene Hopene Cyclase (SHC) polypeptide. Claims 2, 4-5, 8, and 10-11 have been canceled. Claims 14 and 15 have been newly added.
Claims 1, 3, 6-7, 9, and 12-15 are examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of U.S. Application No. PCT/US2021/071351, filed on September 2, 2021. The instant application claims priority under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) to U.S. Provisional Application 63/073633, filed on September 2, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 1, 2023 is in compliance with the provisions of 37 CFR 1.97 and is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 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, they have not been considered.
Withdrawn Objections to the Specification
Applicant indicates that paras. [0011] and [0041] of the amended specification submitted on filed on October 15, 2025 correspond to paras. [0009] and [0039] of the specification filed on March 2, 2023 which recite SEQ ID NO:1. In view of Applicant’s amendments to the specification to remove reference to SEQ ID NO:1, this rejection has been withdrawn.
Withdrawn Claim Rejections - 35 USC § 112(b)
Claims 7-9 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Applicant has amended claim 7 to clarify the instantly claimed SHC polypeptide includes at least 5 amino acid alterations relative to SEQ ID NO:2 and claim 9 to further clarify the amino acid alterations, therefore the rejections of claim 7 and 9 have been withdrawn. Applicant has canceled claim 8 rendering the rejection to these claims moot.
Withdrawn Claim Rejections - 35 USC § 112(d)
Claims 8 and 9 were are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant has canceled claim 8 rendering this rejection moot. Applicant has amended claim 9 as well as claim 7 from which claim 9 depends in order to clarify the claimed amino acid alterations therefore the rejection of claim 9 has been withdrawn.
Withdrawn Claim Rejections - 35 USC § 102
Claims 7-11 were rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Moody et al. (WO 2018/157021 A1, found in IDS, hereafter “Moody”). Applicant has canceled claims 8, 10, and 11 rendering the rejection of these claims moot. Applicant has amended claim 7 to recite that the instantly claimed SHC polypeptide includes at least 5 amino acid alterations relative to SEQ ID NO:2 at position 166, 222, 223, 226, 227, 242, 249, 504, 574, 640, 641, 676, 677, 682 which is not disclosed by Moody. Therefore, this rejection is withdrawn.
New Claim Objections
This is a new objection necessitated by Applicant’s amendment.
Claims 1, 7, and 14-15 are objected to because of the following informalities:
Claims 1 and 7 recite the phrase “…selected from P166X (silent), V222X (substitution), K223X (substitution), E226X (substitution), D227X (substitution), S242X (substitution), R249X (silent), R504X (substitution), A574X (silent), L640X (substitution), P641IX (substitution), M676X (substitution), M677X (substitution) and S682X (substitution)”. Since the wherein clause defining the specific alterations at positions 166, 222, 223, 226, 227, 242, 249, 504, 574, 640, 641, 676, 677, and 682 define which alterations are silent and which are substitutions, the parenthetical indicators of silent and substitution following each position is considered redundant.
Claims 1 and 7 appear to be missing the conjunction “or” before the final amino acid position in the listing of amino acid positions which comprise alterations relative to SEQ ID NO:2. It is recommended that Applicant amend such that claims 1 and 7 recite “…position…677, or 682…”.
Claims 14 and 15 appear to be missing the word “the” in the recited phrase “...includes at least following amino acid alterations”. It is recommended that Applicant amend such that claims 14 and 15 recite “… at least the following…”.
New Claim Rejections - 35 USC § 112
This is a new rejection necessitated by Applicant’s amendment.
Claims 1-15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Dependent claims 6 and 12-13 are similarly rejected based on their dependency from a rejected claim while failing to correct the deficiency.
Claims 1 and 7 recite “at least 5 amino acid alterations” in line 3, “the alterations” in line 5, and “the amino acid alterations” in line 29. As claimed, it is unclear whether all recitations of amino acid alterations are intended to refer to the at least 5 amino acid alterations. Additionally, claims 1 and 7 recite “alterations” in line 5 which appear to comprise silent and substitutions, followed by recitation of “amino acid substitutions” in line 25, followed by recitation of “the amino acid alterations” in line 29 which is linked to functional language regarding the effect of the amino acid alterations on the activity of the SHC polypeptide. The recitation of both alterations and substitutions in the same claim as well as functional language which is limited to the effect of the amino acid alterations, but not the amino acid substitutions, renders the scope of the claim unclear. Appropriate correction is required.
Claims 1 and 7 recite the limitation “the alterations” in line 5. There is insufficient antecedent basis for this limitation in the claim as the prior recitation is to “at least 5 amino acid alterations”. As claimed it is unclear whether “the alterations” is intended to refer to the previously recited alterations, especially as line 29 refers to “the amino acid alterations”. Appropriate correction is required.
Claim 3, which depends from claim 1, recites the limitation "the amino acid alterations" in lines 1-2. Claim 1 recites “at least 5 amino acid alterations” in line 3, “the alterations” in line 5, and “the amino acid alterations” in line 29, which renders the subsequent recitations of “the amino acid alterations” unclear. Appropriate correction is required.
Claim 9, which depends from claim 7, recites the limitation "the amino acid alterations" in lines 1-2. Claim 1 recites “at least 5 amino acid alterations” in line 3, “the alterations” in line 5, and “the amino acid alterations” in line 29, which renders the subsequent recitations of “the amino acid alterations” unclear. Appropriate correction is required.
Claim 14, which depends from claim 1, recites the limitation "amino acid alterations" in line 2. Claim 1 recites “at least 5 amino acid alterations” in line 3, “the alterations” in line 5, and “the amino acid alterations” in line 29, which renders the subsequent recitations of “amino acid alterations” unclear. Appropriate correction is required.
Claim 15, which depends from claim 7, recites the limitation "amino acid alterations" in line 2. Claim 7 recites “at least 5 amino acid alterations” in line 3, “the alterations” in line 5, and “the amino acid alterations” in line 29, which renders the subsequent recitations of “the amino acid alterations” unclear. Appropriate correction is required.
New Claim Rejections - 35 USC § 103
This is a new rejection necessitated by Applicant’s amendment. However, this rejection shares substantial similarity to the rejection as previously set forth in the office action dated November 4, 2025. Any aspect of Applicant’s traversal that pertains to the rejection as newly set forth will be provided following the new statement of rejection.
Claims 1, 3, 6-7, 9, 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over Moody et al. (WO 2018/157021 A1, found in IDS, hereafter “Moody”).
Applicant’s instantly claimed Squalene Hopene Cyclase (SHC) polypeptide having at least 90% sequence identity to SEQ ID NO: 2 comprises at least five amino acid alterations relative to SEQ ID NO: 2 at position 166, 222, 223, 226, 227, 242, 249, 504, 574, 640, 641, 676, 677, or 682. Applicant further claims that amino acid alterations at three positions 166, 249, and 574 are silent which results in an SHC polypeptide which is indistinguishable from the an SHC having SEQ ID NO:2. Thus, Applicant’s SHC polypeptide as instantly claimed only requires amino acid substitutions at two positions which could be any of positions 222, 223, 226, 227, 242, 504, 640, 641, 676, 677, or 682 if the other three amino acid “alterations” are at positions 166, 249, and 574 and are therefore structurally indistinct from SEQ ID NO: 2. Further, Moody teaches wherein the SHC can have an amino acid substitution comprising V45I, V45Q, V45L, E46H, E46Q, Q54E, S86A, F139L, Y142R, Q178E, M184A, M184L, M184I, M184V, R194Q, G239V, I278V, I278T, T326S, L335F, E386Q, 1455T, F460A, Q603H, G623A, G623V, F624Y, F624A, L656E, Y658F, or a combination thereof (Para. [0022]).
With regard to claims 1, 3, 7 and 9, Moody teaches a recombinant vector comprising a nucleic acid molecule encoding a Squalene Hopene Cyclase (SHC) polypeptide having at least 90% identity to SEQ ID NO: 2 and a recombinant SHC polypeptide having at least 90% sequence identity to SEQ ID NO: 2 (Para. [0004]), which shares 100% homology to instantly claimed SEQ ID NO: 2. Additionally, Moody teaches a process for rational design of SHC mutants including the identification of positions E226 and D227 as specificity determining positions (Para. [0084]) as well as many embodiments of SHC mutants comprising amino acid alterations (Tables 2 and 6) which can alter parameters which increase the activity of SHC (Table 6). Additionally, Moody teaches that position L656 is also a specificity determining position (Para. [0084], line 12) and wherein alterations of position L656, specifically an L656E substitution, are able to improve the Michaelis-Menten complex (See Tables 5 and 6) thus improving the catalytic conversion of homofarnesol to ambroxan (Para. [0085], lines 1-3). Further, Moody teaches wherein the SHC can have an amino acid substitution comprising V45I, V45Q, V45L, E46H, E46Q, Q54E, S86A, F139L, Y142R, Q178E, M184A, M184L, M184I, M184V, R194Q, G239V, I278V, I278T, T326S, L335F, E386Q, 1455T, F460A, Q603H, G623A, G623V, F624Y, F624A, L656E, Y658F, or a combination thereof (Para. [0022]).
Moody is silent as to an the SHC polypeptide including an amino acid alteration, relative to SEQ ID NO:2, at positions 226 and 227, or a combination thereof with position 656, specifically L656E.
However, it would have been obvious to apply the process for rational design of SHC mutants and choose to alter the amino acid sequence at positions 226 and 227 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so because Moody teaches that positions 226 and 227 are specificity determining positions for SHC and that various amino acid alterations at various positions in the SHC polypeptide, including at other specificity determining positions (i.e., 656) can be used to increase the activity of SHC for converting homofarnesol to ambroxan (Para. [0017], lines 1-4), thus providing a greater yield of the end product ambroxan (Para. [0027]). Moody teaches that an SHC comprising an amino acid substitution of L656E improves the Michaelis-Menten complex which improves the conversion of homofarnesol to ambroxan (Tables 6 and 10) and provides support for increased ambroxan production from mutant SHCs comprising more than one amino acid substitution (Fig. 3). A skilled artisan would have had a reasonable expectation of success as Moody teaches that positions 226, 227, and 656 are specificity determining positions and that an amino acid substitution of L656E can improve the activity of SHC mutants as well as that multiple amino acid substitutions can increase activity of SHC mutants.
Moody is silent as to the specific substitutions of E226V and D227T (see claims 3 and 9).
However, Moody teaches an SHC polypeptide comprising amino acid substitutions, discloses positions 226 and 227 as specificity determining positions, and further teaches that various amino acid substitutions at various positions can increase the activity of SHC, thus producing more of the end product ambroxan (Fig. 3, Tables 6 and 10). Moody does not specifically teach the instantly claimed substitutions but does provide support for amino acid substitutions at many positions and identifies positions 226 and 227 as specificity determining positions. Since there are only 19 other choices for any specific amino acid substitution and Moody teaches that many amino acid substitutions at many positions lead to increased activity of mutant SHC (Tables 6 and 10, Fig. 3), one having ordinary skill in the art could have pursued the limited number of known potential solutions and easily arrived at the specific instantly claimed substitution of E226V and D227T with a reasonable expectation of success.
Independently, MPEP 3131.02(III) states:
A reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination." Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381, 114 USPQ2d 1250, 1254 (Fed. Cir. 2015) (quoting In re Petering, 301 F.2d 676, 681(CCPA 1962)).
In re Petering, the prior art disclosed a generic chemical formula "wherein X, Y, Z, P, and R'- represent either hydrogen or alkyl radicals, R a side chain containing an OH group." The court held that this formula, without more, could not anticipate a claim to 7-methyl-9-[d, l'-ribityl]-isoalloxazine because the generic formula encompassed a vast number and perhaps even an infinite number of compounds. However, the reference also disclosed preferred substituents for X, Y, Z, P, R, and R' as follows: where X, P, and R' are hydrogen, where Y and Z may be hydrogen or methyl, and where R is one of eight specific isoalloxazines. The court determined that this more limited generic class consisted of about 20 compounds. The limited number of compounds covered by the preferred formula in combination with the fact that the number of substituents was low at each site, the ring positions were limited, and there was a large unchanging structural nucleus, resulted in a finding that the reference sufficiently described "each of the various permutations here involved as fully as if he had drawn each structural formula or had written each name." The claimed compound was 1 of these 20 compounds. Therefore, the reference "described" the claimed compound and the reference anticipated the claims.
Although Moody does not specifically teach amino acid alterations of E226V and D227T, based on the generic disclosure of positions 226 and 227 as specificity determining positions and the fact that there are only 19 options for any amino acid substitution at any position the claimed species can be “at once envisaged” from the limited number of species (19) available based on the generic disclosure of amino acid substitutions at positions 226 and 227.
With regard to claim 6, as detailed above, Moody teaches a recombinant vector comprising a nucleic acid molecule encoding a Squalene Hopene Cyclase (SHC) polypeptide having at least 90% identity to SEQ ID NO: 2 which shares 100% homology to instantly claimed SEQ ID NO: 2 (Para. [0004]) and a process for process for rational design of SHC mutants which makes obvious generation of a nucleic acid sequence encoding an SHC polypeptide including an amino acid alteration at specificity determining positions 226 and 227 in addition to a L656E substitution (another specificity determining position) which would lead to increased SHC activity. Additionally, Moody teaches a recombinant host cell comprising the recombinant SHC vector comprising a nucleic acid molecule encoding an SHC polypeptide which can comprise amino acid substitutions. (Para. [0004], lines 9-10).
With regard to claims 12 and 13, as detailed above, Moody teaches a recombinant vector comprising a nucleic acid molecule encoding a Squalene Hopene Cyclase (SHC) polypeptide having at least 90% identity to SEQ ID NO: 2 which shares 100% homology to instantly claimed SEQ ID NO: 2 (Para. [0004]) and a process for process for rational design of SHC mutants which makes obvious generation of a nucleic acid sequence encoding an SHC polypeptide including an amino acid alteration at specificity determining positions 226 and 227 in addition to a L656E substitution (another specificity determining position) which would lead to increased SHC activity. Moody also teaches a recombinant host cell comprising a recombinant SHC vector (Para. [0004]). Moody further discloses a method of producing ambroxan comprising providing homofarnesol to a recombinant host cell that expresses SHC and collecting ambroxan produced by the host cell comprising SHC (Claim 5). Moody additionally discloses wherein the homofarnesol comprises (3E, 7E) homofarnesol (Claim 8).
Allowable Subject Matter
Claims 14 and 15 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Response to Arguments
Applicant's arguments filed April 2, 2026 have been fully considered but they are not persuasive.
A new ground of rejection necessitated by Applicant’s amendment has been supplied. Applicant has amended claims 1 and 7 to more clearly define the amino acid alterations instantly claimed polypeptide and traverses that Moody fails to teach or suggest the instantly claimed features.
Claims 2, 4-5, 8 and 10-11 have been canceled rendering rejections of those claims moot. Applicant’s traversal has been fully considered but is not persuasive based on the new grounds of rejection as detailed above.
New Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 6-7, 9, and 12-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 3 of U.S. Patent No. 11,0917,52 in view of by Moody et al. (WO 2018/157021 A1, found in IDS, hereafter “Moody”).
Claims 1-3 of U.S. Patent No. 11,0917,52 teach a recombinant vector comprising a nucleic acid molecule encoding SHC wherein the amino acid sequence is SEQ ID NO: 2 or has at least 90% identity to SEQ ID NO: 2, which shares 100% homology to instantly claimed SEQ ID NO: 2; and comprises amino acid substitutions relative to SEQ ID NO: 2 at position 45, 46, 54, 86, 139, 142, 178, 184, 194, 239, 278, 326, 335, 386, 455, 460, 603, 623, 624, 656, 658, or a combination thereof; a recombinant host cell comprising a vector of claim 1; and a method of making ambroxan comprising use of the recombinant host cell of claim 2.
However, U.S. Patent No. 11,0917,52 does not claim all the features of the claimed invention, specifically wherein the recombinant vector comprising a nucleic acid molecule encoding an SHC polypeptide having at least 90% sequence identity to SEQ ID NO:2 includes at least 5 amino acid alterations at position 166, 222, 223, 226, 227, 242, 249, 504, 574, 640, 641, 676, 677, or 682; wherein the amino acid alterations are selected from P166X, V222X, K223X, E226X, D227X, S242X, R249X, R504X, A574X, L640X, P641IX, M676X, M677X, and S682X; wherein X in P166X is P; X in V222X is D, E, N, Q, H, K, or R; X in K223X is S, C, U, T, or M; X in E226X is G, A, V, L, or I; X in D227X is S, C, U, T, or M; X in S242X is H, K, or R; X in R249X is R; X in R504X is S, C, U, T, or M; X in A574X is A; X in L640X is G, A, V, L, or I; X in P641X is S, C, U, T, or M; X in M676X is G, A, V, L, or I; X in M677X is D, E, N, or Q; and X is S682X is H, K, or R; and wherein the Squalene Hopene Cyclase (SHC) polypeptide further includes one or more amino acid substitutions, relative to SEQ ID NO:2, selected from V45I, V450, V45L, E46H, E46Q, 054E, S86A, F139L, Yl42R, 0178E, M184A, Ml84L, Ml841, M184V, R1940, G239V, 278V,[278T, T326S, L335F, E3860, 1455T, F460A, 0603H, G623A, G623V, F624Y, E624A, L656E, and Y658F; and wherein the amino acid alterations enhance the activity of the SHC polypeptide for converting homofarnesol to ambrox. U.S. Patent No. 11,0917,52 also does not claim a recombinant host cell comprising the instantly claimed recombinant vector or a method of producing ambroxan using the instantly claimed recombinant vector.
However, a recombinant vector comprising a nucleic acid molecule encoding an SHC polypeptide having at least 90% sequence identity to SEQ ID NO:2 including an amino acid alteration as instantly claimed are known in the art. As detailed in the rejections above the teachings of Moody render obvious claims 1, 3, 6-7, 9, and 12-13.
With regard to claims 1, 3, 7, and 9, Moody teaches a recombinant vector comprising a nucleic acid molecule encoding a Squalene Hopene Cyclase (SHC) polypeptide having at least 90% identity to SEQ ID NO: 2 and a recombinant SHC polypeptide having at least 90% sequence identity to SEQ ID NO: 2 (Para. [0004]), which shares 100% homology to instantly claimed SEQ ID NO: 2. Additionally, Moody teaches a process for rational design of SHC mutants including the identification of positions E226 and D227 as specificity determining positions (Para. [0084]) as well as many embodiments of SHC mutants comprising amino acid alterations (Tables 2 and 6) which can alter parameters which increase the activity of SHC (Table 6). Additionally, Moody teaches that position L656 is also a specificity determining position (Para. [0084], line 12) and wherein alterations of position L656, specifically an L656E substitution, are able to improve the Michaelis-Menten complex (See Tables 5 and 6) thus improving the catalytic conversion of homofarnesol to ambroxan (Para. [0085], lines 1-3). Further, Moody teaches wherein the SHC can have an amino acid substitution comprising V45I, V45Q, V45L, E46H, E46Q, Q54E, S86A, F139L, Y142R, Q178E, M184A, M184L, M184I, M184V, R194Q, G239V, I278V, I278T, T326S, L335F, E386Q, 1455T, F460A, Q603H, G623A, G623V, F624Y, F624A, L656E, Y658F, or a combination thereof (Para. [0022]). Moody makes obvious the combination of alterations at specificity determining positions E226 and D227 in combination with L656E which can be used to increase the activity of SHC for converting homofarnesol to ambroxan (Para. [0017], lines 1-4), thus providing a greater yield of the end product ambroxan (Para. [0027]). Although Moody is silent as to the specific substitutions of E226V and D227T (see claims 3 and 9), however, Moody teaches amino acid various amino acid alterations at various amino acid positions and specifically identified positions 226 and 227. As there are only 19 other choices for any specific amino acid substitution and Moody teaches that many amino acid substitutions at many positions lead to increased activity of mutant SHC (Tables 6 and 10, Fig. 3), one having ordinary skill in the art could have pursued the limited number of known potential solutions and easily arrived at the specific instantly claimed substitution of E226V and D227T with a reasonable expectation of success.
Therefore, it would have been obvious to one having ordinary skill in the art, to apply the process for rational design of SHC mutants to the recombinant vector claimed in U.S. Patent No. 11,0917,52 which comprises amino acid alterations at position 45, 46, 54, 86, 139, 142, 178, 184, 194, 239, 278, 326, 335, 386, 455, 460, 603, 623, 624, 656, 658, or a combination thereof and choose to also alter the amino acid sequence at positions 226 and 227 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so because Moody teaches that positions 226 and 227 in addition to position 656 are specificity determining positions for SHC and various amino acid alterations at various positions in the SHC polypeptide, including at other specificity determining positions (i.e., 656) can be used to increase the activity of SHC for converting homofarnesol to ambroxan (Para. [0017], lines 1-4), thus providing a greater yield of the end product ambroxan (Para. [0027]). Moody also specifically teaches that an L656E substitution improve the Michaelis-Menten complex (Table 6) thus improving the catalytic conversion of homofarnesol to ambroxan (Para. [0085], lines 1-3).
With regard to claim 6, U.S. Patent No. 11,0917,52 claims a recombinant host cell comprising a recombinant vector comprising a nucleic acid molecule encoding SHC wherein the amino acid sequence comprises amino acid substitutions at position 45, 46, 54, 86, 139, 142, 178, 184, 194, 239, 278, 326, 335, 386, 455, 460, 603, 623, 624, 656, 658, or a combination thereof. As detailed above, Moody makes obvious a vector comprising amino acid substitutions at other positions, specifically positions 226 and 227, as well as the specific substation of L656E, and provides support for use of multiple amino acid substitutions in a single recombinant vector in order to generate an SHC with increased activity.
Therefore, it would have been obvious to substitute the vector as taught U.S. Patent No. 11,0917,52 comprising a nucleic acid molecule encoding an SHC polypeptide which can comprise amino acid substitutions at position 45, 46, 54, 86, 139, 142, 178, 184, 194, 239, 278, 326, 335, 386, 455, 460, 603, 623, 624, 656, 658, or a combination thereof which can be used in recombinant host cell taught in U.S. Patent No. 11,0917,52, with the vector comprising amino acid substitutions of E226V, D227T, and L656E as taught by Moody with a reasonable expectation of success. As U.S. Patent No. 11,0917,52 teaches a recombinant host cell comprising a vector comprising amino acid substitutions at position 45, 46, 54, 86, 139, 142, 178, 184, 194, 239, 278, 326, 335, 386, 455, 460, 603, 623, 624, 656, 658, or a combination thereof which then can further be comprised in a host cell and Moody makes obvious the claimed amino acid substitutions including at positions 226 and 227 which can be used to generate an SHC with increased activity, a skilled artisan would have been motivated to use the vector as taught by the combination of U.S. Patent No. 11,0917,52 and Moody in the recombinant host cell claimed in U.S. Patent No. 11,0917,52 in order to generate a host cell comprising a vector encoding an SHC polypeptide comprising an amino acid alterations of E226V, D227T, and L656E which are able to produce more ambroxan.
With regard to claims 12 and 13, U.S. Patent No. 11,0917,52 claims a method of producing ambroxan comprising providing homofarnesol to a recombinant host cell that expresses SHC wherein the amino acid sequence is SEQ ID NO: 2 or has at least 90% identity to SEQ ID NO: 2, which shares 100% homology to instantly claimed SEQ ID NO: 2; and comprises amino acid substitutions relative to SEQ ID NO: 2 at position 45, 46, 54, 86, 139, 142, 178, 184, 194, 239, 278, 326, 335, 386, 455, 460, 603, 623, 624, 656, 658, or a combination thereof and collecting ambroxan produced by the host cell comprising SHC. U.S. Patent No. 11,0917,52 additionally claims wherein the homofarnesol comprises (3E, 7E) homofarnesol. As detailed above, Moody makes obvious a vector comprising amino acid substitutions at other positions, specifically positions 226 and 227, as well as the specific substation of L656E, and provides support for use of multiple amino acid substitutions in a single recombinant vector in order to generate an SHC with increased activity as well as a recombinant host cell comprising that vector.
Therefore, it would have been obvious to use the recombinant host cell comprising an SHC polypeptide vector comprising amino acid substitutions of E226V, D227T, and L656E as taught by Moody in the method of producing ambroxan comprising use of a recombinant host cell expressing an SHC having amino acid alterations as taught U.S. Patent No. 11,0917,52 via with a reasonable expectation of success. As U.S. Patent No. 11,0917,52 teaches a recombinant host cell comprising a vector comprising amino acid substitutions at position 45, 46, 54, 86, 139, 142, 178, 184, 194, 239, 278, 326, 335, 386, 455, 460, 603, 623, 624, 656, 658, or a combination thereof which then can further be used for ambroxan production and Moody makes obvious an host cell comprising a vector encoding an SHC polypeptide comprising amino acid alterations of E226V, D227T, and L656E which are able to produce more ambroxan, a skilled artisan would have been recognized that the recombinant SHC polypeptide vector comprising amino acid substitutions of E226V, D227T, and L656E as taught by Moody could be used in the method of making ambroxan as taught by U.S. Patent No. 11,0917,52 in order to produce increased quantities of ambroxan.
Response to Arguments
Applicant's arguments filed April 2, 2026 have been fully considered but they are not persuasive.
A new ground of rejection necessitated by Applicant’s amendment has been supplied. Applicant has amended claims 1 and 7 to more clearly define the amino acid alterations instantly claimed polypeptide and traverses that claim 1 and dependent claims are distinct from claims 1-3 of U.S. Patent 11,091,752.
Claims 2, 4-5, 8 and 10-11 have been canceled rendering rejections of those claims moot.
Applicant’s traversal has been fully considered but is not persuasive based on the new grounds of rejection as detailed above.
Conclusion
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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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631
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