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
1. Preliminary amendment and claims 1-14 filed 4/12/24 are present and under consideration.
2. IDS filed 4/12/24 is considered. A signed copy of the IDS is provided with this Office Action.
3. Priority
Applicant’s claim for domestic priority under 35 U.S.C. 119(e), filed 10/19/21, is acknowledged.
Receipt is acknowledged of papers (foreign priority filed 10/26/21) submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
4. Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
5. Claim Objections
Claims 9 & 10-14 are objected to because of the following informalities:
Claim 9 begins with “Process”, and substituting with “A process” will overcome this objection.
Each of Claims 10-14 recites on line 1 “Process according to”. It is suggested to replace each of the claims with “The process of claim ….”.
Appropriate correction is required.
6 Written Description
Claims 1-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-14 of the instant application are drawn to the following genus claims.
1. A retinol-producing host cell expressing a retinol dehydrogenase 22 (RDH22) homolog with at least about 30% identity to a polynucleotide according to SEQ ID NO: 1 or 4, wherein the host cell has been transformed with said polynucleotide encoding said RDH22 homolog and wherein the percentage of dihydroretinoids in a mix of retinoids produced using said host cell under suitable culture conditions is less than about 10% based on total retinoids.
2. The retinol-producing host cell according to claim 1, wherein said process furthermore comprises acetylation of retinol into retinyl acetate.
3. The retinol-producing host cell according to claim 2, wherein the percentage of retinyl acetate in said mix is at least about 80% based on total retinoids.
4. The retinol producing host cell according to claim 1, wherein the percentage of retinal in said mix is less than about 8% based on total retinoids.
5. The retinol-producing host cell according to claim 4, wherein the percentage of retinal is reduced to less than about 1% based on total retinoids.
6. The retinol producing host cell according to claim 1, wherein said mix of retinoids comprises trans and cis-isomers and wherein the percentage of trans-isomers is at least about 80% based on total cis and trans-isomers in said mix.
7. The retinol-producing host cell according to claim 1, wherein the RDH22 homolog is obtained from Yarrowia or Wickerhamomyces.
8. The retinol-producing host cell according to claim 1, furthermore expressing a retinol dehydrogenase 12 (RDH12) homolog.
9. Process for the production of a retinoid-mix comprising cultivation of a retinol-producing host cell according to claim 1 under suitable culture conditions.
10. Process according to claim 9, wherein said retinoid mix comprises dihydroretinal, dihydroretinol and dihydroretinyl acetate, retinol, retinal, retinyl acetate, and wherein the percentage of dihydroretinoids based on total retinoids is less than 10%.
11. Process according to claim 9, wherein the host cell is cultivated in the presence of a lipophilic solvent.
12. Process according to claim 11, wherein the retinoids are accumulated in the lipophilic solvent and optionally extracted from the lipophilic solvent.
13. Process according to claim 11, wherein the lipophilic solvent is selected from isoparaffins including mixtures of alkanes, cycloparaffin, isoalkanes, cycloalkanes, or dodecanes.
14. Process according to claim 9, wherein the host cell is a fungal host cell.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
“A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus.”). Regents of the University of California v. Eli Lilly & Co., 119, F.3d 1559, 1568, 43 USPQ2d 1398, 1405 (Fed. Cir. 1997).
MPEP § 2163 further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the biomolecule, it is "not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed biomolecule.”
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice …, reduction to drawings …, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.” MPEP 2163.
Furthermore, a “‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure ‘indicates that the patentee has invented species sufficient to constitute the gen[us].’ See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (‘[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.’). ‘A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.’ In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).” MPEP 2163.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163.
In the instant case, the specification describes a single species construct of “A retinol-producing fungal host cell expressing a retinol dehydrogenase 22 (RDH22) homolog with at least 95% identity to a polypeptide of SEQ ID NO: 1 or 4 and having retinol dehydrogenase activity, wherein the host cell has been transformed with the polynucleotide encoding the said RDH22 homolog and wherein the percentage of dihydroretinoids in a mix of retinoids produced using said host cell under suitable culture conditions is less than about 10% based on total retinoids, and a process of producing a retinoid mix comprises dihydroretinal, dihydroretinol and dihydroretinyl acetate, retinol, retinal, retinyl acetate, and wherein the percentage of dihydroretinoids based on total retinoids is less than 10%, and wherein the host cell is cultivated in the presence of a lipophilic solvent”.
No information, beyond the characterization of the single species as mentioned above; has been provided by the applicants, which would indicate that they had possession of the claimed genus of - A retinol-producing host cell expressing a retinol dehydrogenase 22 (RDH22) homolog with at least about 30% identity to a polynucleotide according to SEQ ID NO: 1 or 4, wherein the host cell has been transformed with said polynucleotide encoding said RDH22 homolog and wherein the percentage of dihydroretinoids in a mix of retinoids produced using said host cell under suitable culture conditions is less than about 10% based on total retinoids or the process thereof.
The specification discloses the retinol dehydrogenase 22 (RDH22) homolog of SEQ ID NO: 1 or 4 encoded by the DNA sequence of SEQ ID NO: X, vector, host cell and the method making retinoid mix comprising dihydroretinal, dihydroretinol and dihydroretinyl acetate, retinol, retinal, retinyl acetate, and wherein the percentage of dihydroretinoids based on total retinoids is less than 10%.
A total of zero mutants are described for the retinol dehydrogenase 22 (RDH22) homolog sequence of SEQ ID NO: 1 or 4, each comprising 323 or 319 amino acids respectively. This represents no modification of the sequence of SEQ ID NO: 1 or 4. Hence modifying each of the sequences by 70% is neither described or have been shown to possess the required retinol dehydrogenase activity in order to produce the intended product.
The genus of host cells, polypeptides and the encoding polynucleotides required in the claimed invention is an extremely large structurally and functionally variable genus. While the argument can be made that the recited genus of polypeptides is adequately described by the disclosure of the structures of SEQ ID NO: 1 & 4, with specific structures having the associated function/activity, since one could use structural homology to isolate those polypeptides and the encoding polynucleotides recited in the claims. The art clearly teaches the “Practical Limits of Function Prediction”:
(a) Devos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and (iv) conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that “Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, page 105). Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, page 105). Applicants’ are respectfully directed to the problems associated EC Classification in the section “Transferring the EC Classification enzyme to Non-Enzyme Comparisons”; pages 101-102 and Fig. 2a)-b), highlighting the structural and functional heterogeneity based on EC Classification numbers; as the stereo-specificity, substrate-specificity and catalytic properties vary widely.
(b) Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340) also highlight the difficulties associated with “Prediction of protein function from protein sequence and structure”; “To reason from sequence and structure to function is to step onto much shakier ground”, closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer (page 309, paragraph 4), it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions (page 312, paragraph 5), in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity (page 313, paragraph 4), although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein’s role fundamentally (page 323, paragraph 1).
(c) This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polynucleotides and encoded polypeptides do not necessarily share the same function. For example, Witkowski et al., (Biochemistry 38:11643-11650, 1999), teaches that one conservative amino acid substitution transforms a b-ketoacyl synthase into a malonyl decarboxylase and completely eliminates b-ketoacyl synthase activity.
As stated above, no information beyond the characterization of a single species has been provided by the applicants’, which would indicate that they had possession of the claimed genus of host cells, polypeptides and the encoding polynucleotides. As the claimed genera of polypeptides having widely variable structures and associated function, since minor changes in structure may result in changes affecting function and no additional information (species/variant/mutant) correlating structure with function has been provided. Furthermore, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features” (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895).
Therefore, one skilled in the art cannot reasonably conclude that applicant had possession of the claimed invention at the time the instant application was filed. Applicants are referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
7. Claim Rejections - 35 USC § 112 (second paragraph)
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 1-14 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 pre-AIA the applicant regards as the invention.
Claim 1 recite – “A retinol-producing host cell expressing a retinol dehydrogenase 22 (RDH22) homolog with at least about 30% identity to a polynucleotide according to SEQ ID NO: 1 or 4,….”.
The expressions ‘at least about’ or ‘less than about’ in claims 1 & 3-6 attempts to give both broad and narrow meaning to the scope of the above claims. These claims are unclear.
Claims 2 & 7-14 are included in the rejection for failing to correct the defect present in the base claim(s).
Claim 1 recitation: “30% identity to a polynucleotide according to SEQ ID NO: 1 or 4,….”, is indefinite because SEQ ID Nos. 1 & 4 are polypeptide sequences.
Claims 2-14 are included in the rejection for failing to correct the defect present in the base claim(s).
8. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1-6 & 8-10 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2019/058000 A1. WO 2019/058000 A1 teaches to method to produce retinoids, cells comprising retinal dehydrogenase (ROH) which is capable of converting retinal into retinal and thus reduce retinal and mentions endogenous ROH in Yarrowia. It further mentions Yarrowia lipolytica as expression host to express i.e. acetyltransferases, see e.g. pages 2, 5, 10 and example 2. In WO 2019/058000 A1 only Fusarium fujikuroi RDH12 is explicitly disclosed, leading to 65-90% trans-retinyl acetate, see page 16, with only 2% residual retinal after fermentation, see e.g. example 3, page 24. Dihydroretinoids like dihydroretinol are disclosed in table 3, page 21 and 22.
In particular on page 2, WO 2019/058000 A1 teaches a host cell, particularly a carotenoid-producing host cell, such as a fungal host cell, comprising (1) a stereoselective/trans-selective beta-carotene oxidase (BCO) catalyzing the conversion of beta-carotene to a retinal mix with a percentage of at least 65% present as trans-retinal, and (2) acetyl transferases (ATFs) catalyzing the conversion of retinal to a retinyl acetate mix with a total conversion of at least 10% of retinal acetylated into retinyl esters, particularly retinyl acetate and wherein the ATFs have a preference for acetylation of trans-retinal. Preferably, at least 80% of the retinyl esters are in the form of retinyl acetate, preferably as trans-retinyl acetate.
A carotenoid-producing host cell, particularly fungal host cell, according to the present invention is optionally furthermore comprising (3) (preferably heterologous) retinal dehydrogenase (RDH) which is capable of converting retinal into retinal, particularly with a total conversion of at least about 90% towards generation of retinal.
On page 5 of the cited patent - the terms "retinal reductase", "retinal dehydrogenase", "enzyme having retinal reducing activity" or "RDH" are used interchangeably herein and refer to enzymes [EC 1.1.1.105] which nearly exclusively (90% or more) are capable of catalyzing the conversion of retinal into retinal, i.e. which are capable of catalyzing the conversion of retinal to retinal with a total conversion of at least about 90%, preferably 92, 95, 97, 98, 99 or even 100% towards retinal formation.
Thus, in one embodiment, the present invention is directed to a carotenoid-producing host cell, particularly fungal host cell, comprising polynucleotides encoding BCOs, ATFs, and/or RDHs as defined herein which are optimized for expression in said host cell, with no impact on growth of expression pattern of the host cell or the enzymes. Particularly, a carotenoid-producing host cell is selected from Yarrowia, such as Yarrowia lipolytica, comprising optimized polynucleotide sequences selected from the group consisting of SEQ ID NOs: 2, 4, 5,6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 35, 37 and 39 or sequences with at least 60%, such as e.g. 65, 70, 75, 80, 85, 90, 92, 95, 97, 98, 99% or up to 100% identity thereto. See page 10 of WO 2019/058000 A1.
It may be further noted that since the ROH sequence of D1 is 26.6% identical to SEQ ID NO: 4 and 31% identical to SEQ ID NO:1 of the present application (and thus both are "about" 30% identical), WO 2019/058000 A1 anticipates claim 1.
With respect to product claims 1-6 it is emphasized that a product host cell cannot be characterized and thus limited by a desirable product mix that is produced by said host cell in a process that is not defined in said claims. The process features of said claims are thus in principle not limiting with respect to the claimed scope of said product claims.
Since the methods, the substrates and products as disclosed in WO 2019/058000 A1 fall under the scope of process claims 9 and 10 of the present application and since the ROH sequences used in WO 2019/058000 A1 fall under the scope of product claim 1 and since WO 2019/058000 A1 further discloses process steps which are comparable to process features of the product claims of the present application, see above, the subject matter of claims 1-6 and 8-10 is anticipated by WO 2019/058000 A1, either explicitly or implicitly, since the method is comparable such that comparable products are generated.
9. No claim is allowed.
10. US 20200248151 A1 is cited for information but currently not used in any rejection.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to TEKCHAND SAIDHA whose telephone number is (571)272-0940. The examiner can normally be reached on M-F 8.00-5.30. 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, Robert B Mondesi can be reached on 408 918 7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TEKCHAND SAIDHA/
Primary Examiner, Art Unit 1652
Recombinant Enzymes, Hoteling
Telephone: (571) 272-0940
Fax: (571) 273-0940