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 .
DETAILED ACTION
Claims 13, 14, 22, 23 and 33-37 are canceled.
Claims 1-12, 18, 21, 24-25, and 30-33 are pending.
Election/Restrictions
Applicant’s election of species triptonide, SEQ ID NO: 1, SEQ ID NO: 5, diterpene synthase and Saccharomyces, in the reply filed on 05/11/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Information Disclosure Statement
The information disclosure statements (IDS) filed on 04/27/2023, 11/12/2025, and 02/03/2026 are acknowledged and have been considered.
Drawings
The drawings are objected to because “Figure” should be replaced with “FIG.”. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is incomplete. The incorporation by reference paragraph should include the file name “18022026_1_1.txt”, the date of creation “02/17/2023”, and the size “130251 bytes”.
Required response - Applicant must:
• Provide 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.
Specification
The disclosure is objected to because of the following informalities: “Figure” on pages 4-6, 38, 47, and 49-51 should be replaced with “FIG.”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112The 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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-12, 18, 21, 24-25, and 30-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims require functional homologues having at least 80%, 85%, 90%, 95% or 98% sequence identity to cytochrome P450 enzymes SEQ ID NO: 1 or 2 (TwCYP82D274), SEQ ID NO: 4 (TwCYP71BE86), SEQ ID NO: 3 (TwCYP71BE85), SEQ ID NO: 5 or 76 (TwCYP82D213), SEQ ID NO: 6 (TwCYP82D217), and SEQ ID NO: 7 (TwCYP82D275), and functional homologues having at least 80%, 85%, 90%, 95% or 98% sequence identity to SEQ ID NO: 8 (cytochrome B5 TwB5# 1). The claims require the variants of SEQ ID NO: 1 or 2 to be capable of converting miltiradiene and/or dehydroabietadiene into 14-hydroxydehydroabietadiene. The specification discloses that SEQ ID NO: 5 and SEQ ID NO: 76 are variants with 99.8% sequence identity, and that SEQ ID NO: 1 and SEQ ID NO: 2 are variants with 99.2% sequence identity. The specification does not disclose functional homologues with 80%, 85%, 90%, 95% or 98% sequence identity to the claimed SEQ ID NOs. The specification has not described the preserved residues to retain the activity of the recites enzymes. The specification provides insufficient written description to support the genus encompassed by the claims.
Prior art XP_002510313 (cytochrome P450 CYP82D47 [Ricinus communis], published 05/23/2018) and XP_022752262 (cytochrome P450 CYP82D47-like [Durio zibethinus], published 10/25/2017) teach cytochrome P450 enzymes with sequence identity of 56% to SEQ ID NO:1. However, these sequences are predicted by automated computational analysis. Evidentiary reference Graham (Archives of biochemistry and biophysics 369.1 (1999): 24-29) reports that cytochromes P450 form a very large superfamily of proteins with similar structural fold but have vastly different substrates (Abstract). There is a lack of correlation between the structure of conserved amino acids and the function of converting miltiradiene and/or dehydroabietadiene to 14-hydroxydehydroabietadiene, and producing triptonide in the prior art and in the specification.
In view of the lack of art-recognized structure-function relationship, one of ordinary skill in the art would not predictably envision all the species of the claimed genus of functional homologues having at least 80%, 85%, 90%, 95% or 98% sequence identity to SEQ ID NO: 1-8.
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 1-12, 18, 21, 24-25, 30-33 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 1-2, 4, 7, and 9-11 recite the broad recitation “at least 80% sequence identity”, and the claims also recite “preferably at least 85% sequence identity, preferably at least 90% sequence identity, preferably at least 95% sequence identity, more preferred at least 98% sequence identity thereto, or the mature polypeptide thereof” which is the narrower statement of the range/limitation. Claims 30-32 recite the broad recitation “at least 80% sequence identity” and the claim also recites “preferably at least 85% sequence identity, preferably at least 90% sequence identity, preferably at least 95% sequence identity, preferably at least 96% sequence identity, preferably at least 97% sequence identity, preferably at least 98% sequence identity, or even 100% sequence identity.” The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 1-2, 4, 7, and 9-11 recite the limitation " the cytochrome P450 enzyme TwCYP…". There is insufficient antecedent basis for this limitation in the claims. Applicant may delete “the” at the front of the phrase in order to obviate the rejection.
Claims 1-2, 4, 7, 9-11, and 30-32 recite the limitation "the mature polypeptide". There is insufficient antecedent basis for this limitation in the claims. Applicant may consider amending the claims to replace “the” with “a” in order to obviate the rejection.
Claims 1-2, 4, 7, 9-11, and 30-32 recite the limitation "the mature polypeptide”. Applicant does not define mature polypeptide. The claim is indefinite because it is not clear if mature polypeptide is the same sequence as the recited SEQ ID No., or a different sequence.
Claim 6 recites the limitation "said second heterologous nucleic acid" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 8 recites the limitation "said second heterologous nucleic acid" and “said third heterologous nucleic acid” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
Claim 12 recites “wherein the recombinant host cell expresses one or more of a diterpene synthase”. The claim recites a single enzyme. The claim is indefinite because it is not clear what other alternatives are encompassed by the claim. Applicant may consider amending the claim to recite “wherein the recombinant host cell further expresses a diterpene synthase” in order to obviate the rejection.
Claims 31-32 recite the limitation "the polypeptide" in line 2 and line 3, respectively. There is insufficient antecedent basis for this limitation in the claims. Applicant may consider amending the claim to replace “the” with “a” in order to obviate the rejection.
Claim 32 recites “The recombinant host cell according to claim 1 comprising a plasmid, expression vector, expression construct or recombinant host cell”. The claim is indefinite because it is not clear how the recombinant host cell can comprise a recombinant host cell.
Claim 33 recites “The recombinant host cell according to claim 1 comprising the
compound 14-OH-dehydroabietadiene”. The claim is indefinite because it is unclear whether it requires the host cell to comprise 14-OH-dehydroabietadiene before SEQ ID NO: 1 or a functional homologue are expressed.
Claims 3, 5, 18, 21, and 24-25, which depend from claim 1, do not cure the indefiniteness, and are rejected.
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 12, 21, 24, 25 and 30-33 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.
Claim 12 recites “wherein the recombinant host cell expresses one or more of a diterpene synthase”. The claim is not a proper dependent claim because it fails to include all the limitations of claim 1 upon which it depends. Claim 1 does not recite a diterpene synthase. Applicant may consider amending the claim to “wherein the recombinant host cell further expresses a diterpene synthase” in order to obviate the rejection.
Claim 21 does not further limit the subject matter of claim 1. The claim recites wherein the recombinant host cell is capable of producing triptonide. This limitation simply repeats the preamble of claim 1. The limitation “when cultured under conditions suitable for production of said compound” is a recitation of an inherent characteristic associated with the claimed cell. Applicant may consider incorporating this latter limitation at the end of claim 1.
Claims 24 and 25 do not further limit the subject matter of claim 1. The recitations “capable of..” do not further limit the structure of claim 1. Applicant may consider incorporating these wherein clauses at the end of claim 1.
Claims 30-32 do not further limit claim 1. Claim 1 requires the cell to comprise SEQ ID NO: 1 or functional homologue thereof. However, claims 30 and 31 requires the host cell to comprises one of the sequences SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 or functional homologues. Claims 30 and 31 recite SEQ ID NO: 1 as an alternative and do not require the host cell to comprise SEQ ID NO: 1. Applicant may consider amending the claim to delete “one of the sequences” in order to obviate the rejection.
Claim 33 does not further limit the subject matter of claim 1 because the compound 14-OH-dehydroabietadiene is already recited at the end of ii) of claim 1.
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 § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-12, 21, 24-25, and 30-33 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception of laws of nature, natural phenomena, and products of nature (a nature-based product) without significantly more.
The claims recite a cell capable of producing triptonide (Step 1: YES) comprising cytochrome P450 enzyme TwCYP82D274 as set forth in SEQ ID NO:1. Tripterygium wilfordii is a plant comprising cells that comprise TwCYP82D274 with SEQ ID NO: 1 (See specification page 6 lines 16-17, page 32 last para.). Evidentiary reference Kunhao (cited in 102 rejection) reports that 14-hydroxy-dehydroabietadiene is a precursor in biosynthesis pathway of triptolide in Tripterygium wilfordii and is vital for the production of triptolide and related diterpenes (Abstract, Introduction). Applicant discloses SEQ ID NOs: 2-9 are derived from Tripterygium wilfordii (See specification page 6 lines 22-35). Since the cell of Tripterygium wilfordii naturally comprises the enzymes set forth as SEQ ID NOs: 1-8, it is understood that the cell is capable of producing 14 hydroxydehydroabietadiene, 3, 14- dihydroxydehydroabietadiene, 3, 14 dihydroxyabeodiene, 14-hydroxy-18-aldo-abeodiene, triptophenolide and triptonide. The claimed product lacks markedly different characteristics and is a product of nature (Step 2A prong 1: YES). This judicial exception is not integrated into a practical application because producing a recombinant cell is well-understood, routine, conventional activity in the field and is nothing more than an attempt to generally link the product of nature to a particular technological environment (Step 2A prong 2: NO). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (Step 2B: NO).
Applicant may consider amending claim 1 to incorporate the limitation of claim 18 in order to obviate the rejection.
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.
Claims 1-12, 21, 24-25, and 30-33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tu (Nature Communications 11.1 (2020): 971, of record in IDS), as evidenced by Forman (Molecules 22.6 (2017): 981) and Kunhao (Microbial Cell Factories, 25:41, 2026)
Using the broadest reasonable interpretation, claim 1 is interpreted as being drawn to a cell comprising cytochrome P450 enzyme TwCYP82D274 as set forth in SEQ ID NO: 1 or a functional homologue thereof having at least 80% sequence identity. The limitations of “recombinant” and “heterologous” are product by process limitations. Determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. See MPEP 2113.
Regarding claims 1 and 33, Tu teaches sequencing the genome of a cell of Tripterygium wilfordii (Title) and teaches that Tripterygium wilfordii is capable of producing miltiradiene (FIG. 4). Applicant discloses that Tripterygium wilfordii comprises SEQ ID NO: 1 (Specification page 32 last para, page 6 lines 16-17). The limitations “capable of producing triptonide, miltiradiene and/or dehydroabietadiene” and “capable of converting miltiradiene and/or dehydroabietadiene into 14 hydroxydehydroabietadiene” are intended use limitations. Evidentiary reference Forman reports that T. wilfordii comprises dehydroabietadiene (Figure 1 legend). Evidentiary reference Kunhao reports that T. wilfordii comprises 14-hydroxy-dehydroabietadiene (Abstract).
Regarding claims 2-11 and 30-32, Applicant discloses that Tripterygium wilfordii comprises the enzymes set forth as SEQ ID NOs: 1-8 (Specification page 6 lines 22-35). Thus, it is understood that the cell is capable of producing 14 hydroxydehydroabietadiene, 3, 14- dihydroxydehydroabietadiene, 3, 14 dihydroxyabeodiene, 14-hydroxy-18-aldo-abeodiene, triptophenolide, triptonide, and triptolide, since these enzymes are involved in the triptolide production pathway.
Regarding claim 12, Tu teaches that T. wilfordii comprises diterpene synthases such as CPP synthase (CPS1) and miltiradiene synthase (MS) (page 2 left column second para., page 4 left column third para.).
Regarding claims 21 and 24-25, evidentiary reference Kunhao reports that T. wilfordii comprises triptonide (page 1 right column first line).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY A CRUM whose telephone number is (571)272-1661. The examiner can normally be reached M-F 8:00-5:00 CT with alternate Fridays off.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, LOUISE W HUMPHREY can be reached at 571-272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARY A CRUM/Examiner, Art Unit 1657
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
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