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 .
Status of the Claims
Claims 1-13 are pending and 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.
Objections to the Specification
The disclosure is objected to because Paragraphs 0009 and 0039 state that the nucleotide sequence of wild-type GmSHC is provided in SEQ ID NO:1.
However, although SEQ ID NO:1 is part of the “Sequence Listing” filed 10/15/2025, no nucleotide sequence for wild-type GmSHC is provided.
“Sequence Listing” is Defective
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specifically, the “Sequence Listing” filed 10/15/2025 is defective because no nucleotide sequence has been provided for SEQ ID NO: 1.
Required response – Applicant must provide:
• A replacement "Sequence Listing" part of the disclosure, as described above in item 1); together with
• An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2);
• A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
• If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
o A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
- A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
- A copy of the amended specification without markings (clean version); and
- A statement that the substitute specification contains no new matter and
- An amendment to the specification to remove the “Sequence Listing previously submitted as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3))
• If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, Applicant must also provide:
o A CRF in accordance with 1.821(e)(1) or 1.821(e)(2) as required by 37 CFR 1.825(b)(6)(ii); and
o Statement according to item 2) a) or b) above.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7-9 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.
Claims 7-9 recite limitations wherein a recombinant Squalene Hopene Cyclase (SHC) polypeptide having at least 90% sequence identity to SEQ ID NO:2 and including an amino acid alteration, relative to SEQ ID NO:2, at position 166, 222, 223, 226, 227, 242, 249, 504, 574, 640, 641, 676, 677, 682 or a combination thereof (in claim 7); wherein the amino acid alteration comprises a synonymous amino acid at position 166, 249 or 574 or amino acid substitution at position 222, 223, 226, 227, 242, 504, 640, 641, 676, 677, or 682 (in claim 8); and wherein the amino acid alteration comprises P166P, V222Q, V222R, K223S, E226V, D227T, S242R, R249R, R504C, A574A, L640G, P641S, M676L, M677E, S682R, or a combination thereof (in claim 9). Embodiments of these claims include wherein the claimed amino acid alteration specifically the synonymous amino acids at position 166, 249, and 574 of P166P, R249R, and A574A respectively, appear to result in an SHC polypeptide which comprises the same sequence as SEQ ID NO: 2 thus rendering the scope of these claims unclear. Appropriate correction is required.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 8 and 9 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.
Specifically, claims 8 and 9 are drawn to a recombinant SHC polypeptide comprising amino acid alterations relative to SEQ ID NO: 2 comprising a synonymous amino acid at position 166, 249, or 574 or amino acid substitution at position 222, 223, 226, 227, 242, 504, 640, 641, 676, 677, or 682 (claim 8) and specifically, amino acid alterations comprising P166P, V222Q, V222R, K223S, E226V, D227T, S242R, R249R, R504C, A574A, L640G, P641S, M676L, M677E, S682R, or a combination thereof (claim 9). Several of the claimed amino acid modifications of the polypeptide, specifically the synonymous amino acids at position 166, 249, and 574 of P166P, R249R, and A574A respectively, appear to result in an SHC polypeptide which comprises the same sequence as SEQ ID NO: 2. Essentially, due to Applicant’s own claim language, these embodiments of claims 8 and 9 are already included in the scope of claim 7. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 7-11 are 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”).
With regard to claims 7-9, Moody discloses a recombinant SHC polypeptide having at least 90% sequence identity to SEQ ID NO: 2 which shares 100% homology to instantly claimed SEQ ID NO: 2 (Para. [0004]). Although Moody does not disclose amino acid alterations at position 166, 222, 223, 226, 227, 242, 249, 504, 574, 640, 641, 676, 677, 682 or a combination thereof comprising a synonymous amino acid at position 166, 249 or 574; and specifically wherein the amino acid alteration comprises P166P, R249R, and/or A574A; the instantly claimed polypeptide comprising synonymous alterations is structurally indistinct from the recombinant polypeptide having at least 90% sequence identity to SEQ ID NO: 2 as disclosed in Moody.
With regard to claims 10 and 11, as detailed above, the instantly claimed recombinant SHC polypeptide comprising synonymous alterations at positions 166, 249, and/or 574 is not structurally different from the recombinant SHC polypeptide disclosed by Moody. Moody also discloses Moody discloses wherein the SHC polypeptide has an amino acid substitution, 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 (Para. [0004]). Further, Moody discloses wherein the SHC has an amino acid substitution comprising V45I, V45Q, V45L, E46H, E46Q, Q54E, S86A, F139L, Y142R, Q178E, M184A, M184L, M184I, M184V, R194Q, G239V, 1278V, T326S, L335F, E386Q, 1455T, F460A, Q603H, G623A, G623V, F624Y, F624A, L656E, Y658F, or a combination thereof (Para. [0022]). Thus, the instantly claimed embodiments wherein the recombinant SHC polypeptide comprise synonymous amino acid alterations are structurally indistinct from the recombinant SHC polypeptide as disclosed in Moody.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-13, are rejected under 35 U.S.C. 103 as being unpatentable over Moody (as above).
With regard to claims 1 and 7, 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 position 226 as a specificity determining position (Para. [0084]) as well as many specific 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 656 is also a specificity determining position (Para. [0084], line 12) and wherein alterations of position 656 are able to improve the Michaelis-Menten complex (Table 6) thus improving the catalytic conversion of homofarnesol to ambroxan (Para. [0085], lines 1-3).
Moody does not provide a preferred embodiment wherein the SHC polypeptide includes an amino acid alteration, relative to SEQ ID NO:2, at position 226, or a combination thereof with position 656.
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 position 226 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so because Moody teaches that position 226 is a specificity determining position 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]).
With regard to claims 2 and 8, as detailed above Moody teaches a recombinant vector comprising a nucleic acid encoding an SHC polypeptide having at least 90% sequence identity to SEQ ID NO: 2 and the recombinant SHC polypeptide having at least 90% sequence identity to SEQ ID NO: 2, both comprising amino acid substitutions (Para. [0004]) as well as teaching position 226 as a specificity determining position (Para. [0084]). Additionally, Moody teaches a process for rational design of SHC mutants including the identification of position 226 as a specificity determining position (Para. [0084]) as well as and many specific embodiments of SHC mutants comprising amino acid alterations (Tables 2 and 6) which can alter parameters which increase the activity of SHC (Table 6). Further, Moody teaches that position 656 is also a specificity determining position (Para. [0084], line 12) and wherein an amino acid substitution at position 656 is able to improve the Michaelis-Menten complex (Table 6) thus improving the catalytic conversion of homofarnesol to ambroxan (Para. [0085], lines 1-3).
Moody does not provide a preferred embodiment wherein the amino acid alteration comprises substitution at position 226.
However, it would have been obvious to apply the process for rational design of SHC mutants and choose to substitute the amino acid at position 226 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so because Moody teaches that position 226 is a specificity determining position for SHC and that various amino acid substitutions 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]).
With regard to claims 3 and 9, as detailed above, Moody teaches a recombinant vector comprising a nucleic acid molecule encoding an SHC polypeptide having at least 90% identity to SEQ ID NO: 2, which shares 100% homology to instantly claimed SEQ ID NO: 2, and a comprising amino acid substitutions. Moody also teaches a recombinant SHC polypeptide having at least 90% sequence identity to SEQ ID NO: 2 and including amino acid substitutions (Para. [0004]). Additionally, Moody teaches a process for rational design of SHC mutants including the identification of position 226 as a specificity determining position (Para. [0084]) and wherein an amino acid substitution at position 656 is able to improve the Michaelis-Menten complex (Table 6) thus improving the catalytic conversion of homofarnesol to ambroxan (Para. [0085], lines 1-3).
Moody does not provide a preferred embodiment wherein the amino acid alterations comprise E226V.
However, Moody teaches an SHC polypeptide comprising amino acid substitutions, discloses position 226 as a specificity determining position, 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 for the identification of position 226 as a specificity determining position. 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 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, based on the generic disclosure of position 226 as a specificity determining position 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 position 226.
With regard to claims 4 and 10, as detailed above, Moody teaches recombinant vector comprising a nucleic acid molecule encoding an SHC polypeptide having at least 90% identity to SEQ ID NO: 2, which shares 100% homology to instantly claimed SEQ ID NO: 2 and a recombinant SHC polypeptide having at least 90% sequence identity to SEQ ID NO: 2 (Para. [0004]). Additionally, Moody teaches a process for rational design of SHC mutants including the identification of position 226 as a specificity determining positions (Para. [0084]). Further, Moody teaches wherein the SHC has an amino acid substitution, 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 (Para. [0004]).
Moody does not provide a preferred embodiment wherein a recombinant vector comprising a nucleic acid molecule encoding an SHC polypeptide having at least 90% identity to SEQ ID NO: 2 and comprising an amino acid alteration at position 226 or a combination thereof, or a recombinant SHC polypeptide having at least 90% sequence identity to SEQ ID NO: 2 and comprising an amino acid alteration at position 226 or a combination thereof and wherein the amino acid alteration further comprises an amino acid substitution 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.
However, Moody does teach a process for rational design of SHC mutants which identified positions 226 and 656 as specificity determining positions (Para. [0084]). As Moody teaches amino acid substitutions at position 656, one of the specificity determining positions, improve the Michaelis-Menten complex which improves the conversion of homofarnesol to ambroxan (Para. [0085], lines 1-3). Thus, amino acid substitutions at one of the specificity determining positions, position 656, generated an SHC which was able to produce more ambroxan. Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to combine the amino acid substitution at position 656 which generated an SHC with increased activity with amino acid substitutions at other specificity determining positions, e.g. position 226, in order to determine whether conversion of homofarnesol to ambroxan by SHC could be increased further. Additionally, Moody 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 and 656 are specificity determining positions and that amino acid alterations in at least one specificity determining position (position 656) can increase the activity of SHC as well as that multiple amino acid substitutions can increase the activity of SHC mutants.
With regard to claims 5 and 11, Moody teaches recombinant vector comprising a nucleic acid molecule encoding an SHC polypeptide having at least 90% identity to SEQ ID NO: 2, which shares 100% homology to instantly claimed SEQ ID NO: 2 and a recombinant SHC polypeptide having at least 90% sequence identity to SEQ ID NO: 2 (Para. [0004]). Additionally, Moody teaches a process for rational design of SHC mutants including the identification of positions 226, 227, and 656 as specificity determining positions (Para. [0084]). Further, Moody teaches wherein the SHC has an amino acid substitution comprising V45I, V45Q, V45L, E46H, E46Q, Q54E, S86A, F139L, Y142R, Q178E, M184A, M184L, M184I, M184V, R194Q, G239V, 1278V, T326S, L335F, E386Q, 1455T, F460A, Q603H, G623A, G623V, F624Y, F624A, L656E, Y658F, or a combination thereof (Para. [0022]).
Moody does not provide a preferred embodiment wherein a recombinant vector comprising a nucleic acid molecule encoding an SHC polypeptide having at least 90% identity to SEQ ID NO: 2 and comprising an amino acid alteration at position 226 or a recombinant SHC polypeptide having at least 90% sequence identity to SEQ ID NO: 2 and comprising an amino acid alteration at position 226 and wherein the amino acid alteration further comprises an amino acid substitution comprising V45I, V45Q, V45L, E46H, E46Q, Q54E, S86A, F139L, Y142R, Q178E, M184A, M184L, M184I, M184V, R194Q, G239V, 1278V, T326S, L335F, E386Q, 1455T, F460A, Q603H, G623A, G623V, F624Y, F624A, L656E, Y658F, or a combination thereof.
However, Moody does teach a process for rational design of SHC mutants which identified positions 226 and 656 as specificity determining positions (Para. [0084]). Moody specifically teaches 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). Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to combine the specific amino acid substitution of L656E which generates an SHC with increased activity with amino acid substitutions at other specificity determining positions, e.g. position 226, in order to determine whether conversion of homofarnesol to ambroxan by SHC could be further increased by additional amino acid modifications. Additionally, Moody 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 and 656 are specificity determining positions and that specifically an amino acid substitution of L656E can improve the of SHC as well as that multiple amino acid substitutions can increase activity of SHC mutants.
With regard to claim 6, as detailed above in claim 1, 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 position 226 which could 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).
Moody does not provide a preferred embodiment a recombinant host cell comprising a recombinant SHC vector comprising a nucleic acid molecule encoding an SHC polypeptide including amino acid alteration, relative to SEQ ID NO:2, at position 226.
However, it would have been obvious to substitute the vector as taught by Moody 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 with the instantly claimed vector comprising amino acid alterations at position 226 (as made obvious in claim 1 above) with a reasonable expectation of success. One would have been motivated to do so as Moody teaches that amino acid alterations of SHC polypeptides are able to increase the activity of SHC which leads to increased ambroxan production. Thus, the instantly claimed recombinant host cell can be used to generate of SHC polypeptides comprising amino acid alterations which are able to produce more ambroxan.
With regard to claims 12 and 13, as detailed above, Moody teaches a recombinant host cell comprising a recombinant SHC vector comprising a nucleic acid molecule encoding an SHC comprising amino acid substitutions (Para. [0004], lines 9-10). 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).
Moody does not provide a preferred embodiment a method for producing ambroxan comprising the instantly claimed recombinant host cell comprising a recombinant vector comprising a nucleic acid molecule encoding a Squalene Hopene Cyclase (SHC) polypeptide having at least 90% sequence identity to SEQ ID NO:2 and including an amino acid alteration, relative to SEQ ID NO:2, at position 226. However, this instantly claimed recombinant host cell has been made obvious by the teachings of Moody as detailed above in claims 6 and claim 1.
Therefore, it would have been obvious to practice the method of producing ambroxan taught by Moody and substitute the recombinant host cell comprising the recombinant vector comprising a nucleic acid molecule encoding an SHC polypeptide having at least 90% sequence identity to SEQ ID NO:2 and including an amino acid alteration at position 226 as instantly claimed with a reasonable expectation of success. One having ordinary skill would have been motivated to do so because Moody teaches both recombinant vectors comprising nucleic acid sequences encoding SHC polypeptides comprising amino acid alterations can be used to produce ambroxan and that an amino acid alterations of SHC polypeptides at various positions (including those as instantly claimed and made obvious in claim 1) are able to increase the activity of SHC which leads to increased ambroxan production. Thus, the instantly claimed recombinant host cell of claim 6 could be used in Moody’s method of ambroxan production in order to produce increased quantities of ambroxan.
Double Patenting
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).
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Claims 1-6 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 an amino acid alteration at position 166, 222, 223, 226, 227, 242, 249, 504, 574, 640, 641, 676, 677, 682 or a combination thereof; wherein amino acid alteration comprises a synonymous amino acid at position 166, 249 or 574 or amino acid substitution at position 222, 223, 226, 227, 242, 504, 640, 641, 676, 677, or 682; and wherein the amino acid alteration comprises P166P, V222Q, V222R, K223S, E226V, D227T, S242R, R249R, R504C, A574A, L640G, P641S, M676L, M677E, S682R, or a combination thereof. 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 1-6 and 12-13.
With regard to claim 1, Moody teaches a process for rational design of SHC mutants including the identification of position 226 as a specificity determining position (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 656 is also a specificity determining position (Para. [0084], line 12) and wherein alterations of position 656 are able to improve the Michaelis-Menten complex (Table 6) thus improving the conversion of homofarnesol to ambroxan (Para. [0085], lines 1-3).
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 and choose to alter the amino acid sequence at position 226 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so because Moody teaches that position 226 is a specificity determining position 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]).
With regard to claim 2, as detailed above Moody teaches a process for rational design of SHC mutants including the identification of position 226 as a specificity determining position (Para. [0084]) as well as and many specific embodiments of SHC mutants comprising amino acid alterations (Tables 2 and 6) which can alter parameters which increase the activity of SHC (Table 6). Further, Moody teaches that position 656 is also a specificity determining position (Para. [0084], line 12) and wherein an amino acid substitution at position 656 is able to improve the Michaelis-Menten complex (Table 6) thus improving the catalytic conversion of homofarnesol to ambroxan (Para. [0085], lines 1-3).
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 which comprises amino acid substitutions claimed in U.S. Patent No. 11,0917,52 and choose to substitute the amino acid at position 226 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so because Moody teaches that position 226 is a specificity determining position for SHC and that various amino acid substitutions 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]).
With regard to claim 3, as detailed above, Moody discloses a process for rational design of SHC mutants including the identification of position 226 as a specificity determining position (Para. [0084]) and wherein an amino acid substitution at position 656 is able to improve the Michaelis-Menten complex (Table 6) thus improving the catalytic conversion of homofarnesol to ambroxan (Para. [0085], lines 1-3).
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 which comprises amino acid substitutions claimed in U.S. Patent No. 11,0917,52 and choose to substitute the amino acid at position 226 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so because Moody teaches that position 226 is a specificity determining position for SHC and that various amino acid substitutions 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]). 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 with a reasonable expectation of success.
With regard to claim 4, U.S. Patent No. 11,0917,52 claims a recombinant vector comprising 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. As detailed above, Moody teaches a process for rational design of SHC mutants which identified positions 226 and 656 as specificity determining positions (Para. [0084]). Moody teaches amino acid substitutions at position 656, one of the specificity determining positions, improve the Michaelis-Menten complex which improves the conversion of homofarnesol to ambroxan (Para. [0085], lines 1-3). Thus, amino acid substitutions at one of the specificity determining positions, position 656, generated an SHC which was able to produce more ambroxan. Moody also provides support for increased ambroxan production from mutant SHCs comprising more than one amino acid substitution (Fig. 3)
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to combine the vector encoding a SHC polypeptide comprising an amino acid substitution at position 656 as claimed in U.S. Patent No. 11,0917,52 and add an amino acid substitution at position 226 as taught by Moody. Since Moody teaches that positions 266 and 656 are specificity determining positions, that amino acid substitutions at position 656 can result in increased ambroxan production, and that multiple amino acid modifications of SHC can also result in increased production, a skilled artisan would have been motivated to combine amino acid alterations at position 226 and 656 in order to generate an SHC with increased ambroxan production and would have had a reasonable expectation of success.
With regard to claim 5, U.S. Patent No. 11,0917,52 claims a recombinant vector comprising 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. As detailed above, Moody teaches a process for rational design of SHC mutants which identified positions 226 and 656 as specificity determining positions (Para. [0084]). Moody teaches that specific amino acid substitutions of V45I, V45Q, V45L, E46H, E46Q, Q54E, S86A, F139L, Y142R, Q178E, M184A, M184L, M184I, M184V, R194Q, G239V, 1278V, T326S, L335F, E386Q, 1455T, F460A, Q603H, G623A, G623V, F624Y, F624A, L656E, Y658F, or a combination thereof could be used to increase SHC activity and specifically teaches 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).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to combine the vector encoding a SHC polypeptide comprising an amino acid substitution at position 656 as claimed in U.S. Patent No. 11,0917,52 with the specific amino acid substitutions as taught by Moody (e.g., L656E) and add an additional amino acid substitution at position 226. Since Moody teaches that positions 266 and 656 are specificity determining positions, that amino acid substitutions at position 656 of L656E can result in increased ambroxan production, and that multiple amino acid modifications of SHC can also result in increased production, a skilled artisan would have been motivated to combine an amino acid alterations at position 226 with a specific alteration of L656E in order to generate an SHC with increased ambroxan production and would have had a reasonable expectation of success.
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 position 226, 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 an additional amino acid substitution at position 226 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 used for ambroxan production and Moody makes obvious additional amino acid substitutions including at position 226 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 an SHC comprising a vector encoding an SHC polypeptide comprising an additional amino acid alterations at positions 226 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 position 226, 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 substitute recombinant host cell used in the method of producing ambroxan as taught U.S. Patent No. 11,0917,52 with the recombinant host cell comprising a SHC polypeptide comprising an amino acid alteration at position 226 with a reasonable expectation of success. One having ordinary skill would have been motivated to do so because U.S. Patent No. 11,0917,52 and Moody both teach recombinant vectors comprising nucleic acid sequences encoding SHC polypeptides comprising amino acid alterations can be used to produce ambroxan and that amino acid alterations of SHC polypeptides at various positions (including those as instantly claimed and made obvious in claim 1, e.g. position 226) are able to increase the activity of SHC which leads to increased ambroxan production. Thus, the instantly