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. Applicant’s election of Group I (claims 1-12, 14-17 & 20-23) in the reply filed on 11/21/25 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 § 818.03(a)).
2. Claims withdrawn:
Claim 13 is withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
3. Priority
Applicant’s claim for domestic priority under 35 U.S.C. 119(e), filed 8/3/22, is acknowledged.
4. Drawings
The drawings filed on 8/3/23 are acknowledged.
5. 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.
6. IDS filed 7/18/24 is acknowledged. A signed copy of the IDS is provided with this Office Action.
7. Claim Rejections - 35 USC § 112, first paragraph (Enablement)
Claims 1-5, 8, 11-12, 14-17 & 20-23 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 1-5, 8, 11-12, 14-17 & 20-23 are drawn to as follows:
1. (Currently Amended) A recombinant Aspergillus niger, comprising an exogenous nucleic acid molecule encoding aspartate 1-decarboxylase (PAND), an exogenous nucleic acid molecule encoding β-alanine-pyruvate aminotransferase (BAPAT), and an exogenous nucleic acid molecule encoding 3- hydroxypropionate dehydrogenase (HPDH).
2. (Original) The recombinant Aspergillus niger of claim 1, wherein the copy number of each of PAND, BAPAT, and HPDH is independently about 1 to about 80 in the recombinant Aspergillus niger.
3. (Original) The recombinant Aspergillus niger of claim 1, wherein the copy number of each of PAND, BAPAT, and HPDH is independently about 10 to about 30 in the recombinant Aspergillus niger.
4. (Currently Amended) The recombinant Aspergillus niger of claim 1, wherein:
i) an ald6a, ald6b, ald3, and/or oahA gene is not present or does not produce a functional product in the recombinant Aspergillus niger; and/or
ii) apyc, aatl, and/or mctl gene is overexpressed in the recombinant Aspergillus niger.
5. (Currently Amended) The recombinant Aspergillus niger of claim 1, wherein an ald6a gene is not present or does not produce a functional product in the recombinant Aspergillus niger, and wherein a pyc gene is overexpressed in the recombinant Aspergillus niger.
6. (Currently Amended) The recombinant Aspergillus niger of claim 1, wherein:i) the exogenous nucleic acid molecule encoding PAND encodes an amino acid sequence comprising at least 95% sequence identity to SEQ ID NO: 1; and/or ii) the exogenous nucleic acid molecule encoding BAPAT encodes an amino acid sequence comprising at least 95% sequence identity to SEQ ID NO: 2; and/or iii) the exogenous nucleic acid molecule encoding HPDH encodes an amino acid sequence comprising at least 95% sequence identity to SEQ ID NO: 3.
7. (Currently Amended) The recombinant Aspergillus niger of claim 1, wherein:
i) the exogenous nucleic acid molecule encoding PAND comprises or consists of a sequence encoding SEQ ID NO: 1; and/or
ii) the exogenous nucleic acid molecule encoding BAPAT comprises or consists of a sequence encoding SEQ ID NO: 2; and/or iii) the exogenous nucleic acid molecule encoding HPDH comprises or consists of a sequence encoding SEQ ID NO: 3.
8. (Original) The recombinant Aspergillus niger of claim 1, wherein the exogenous nucleic acid molecules encoding PAND, BAPAT, and HPDH are operably linked to a promoter.
9. (Currently Amended) The recombinant Aspergillus niger of claim 1, wherein the exogenous nucleic acid molecules encoding PAND, BAPAT, and HPDH are encoded by a nucleic acid molecule comprising at least 95% sequence identity to SEQ ID NO: 4 and/or SEQ ID NO: 142.
10. (Original) The recombinant Aspergillus niger of claim 1, comprising a nucleic acid molecule comprising SEQ ID NO: 4 and/or SEQ ID NO: 142.
11. (Currently Amended) The recombinant Aspergillus niger of claim 1, wherein the exogenous nucleic acid molecules encoding PAND, BAPAT, and HPDH are comprised on a vector.
12. (Original) A method of producing 3-hydroxypropionic acid (3-HP), comprising: culturing the recombinant Aspergillus niger of claim 1 under conditions that permit the production of 3-HP, thereby making 3-HP.
13. (Original) A method of producing 3-HP, comprising: inoculating a media with Aspergillus niger comprising a 3-HP P-alanine pathway, thereby generating a cultured media, and fermenting the cultured media at a temperature of 30°C to 37 °C, under acidic and microaerobic conditions.
14. (Currently Amended) The method of claim 12, wherein the conditions that permit the production of 3-HP comprise fermenting the Aspergillus niger at a temperature of 30 °C to 37 °C, under acidic and microaerobic conditions.
15. (Currently Amended) The method of claim 1413,wherein:_i)the temperature is 33 °C to 35 °C,(ii) the acidic conditions comprise a pH of 1 to 4, and/or (iii) the microaerobic conditions comprise a dissolved oxygen content of less than 15%.
16. (Currently Amended) The method of claim 14, wherein:(i) the temperature is about 34 °C,(ii) the acidic conditions comprise a pH of about 2, and/or (iii) the microaerobic conditions comprise a dissolved oxygen content of less than 0% to about 10%.
17. (Currently Amended) The method of claim 12 wherein culturing comprises culturing the recombinant Aspergillus niger in Riscaldati B medium (RisB).
18-19. (Canceled)
20. (Currently Amended) The method of claim 14, wherein the fermenting is performed in a bioreactor.
21. (Original) A kit, comprising: the isolated recombinant Aspergillus niger of the isolated recombinant Aspergillus niger of a media, carbon source, nutrient additive, antifoam, antibiotic, filter, or combinations thereof.
22. (New) The recombinant Aspergillus niger of claim 1, wherein the recombinant Aspergillus niger produces 3-hydroxypropionic acid (3-HP).
23. (New) The recombinant Aspergillus niger of claim 11, wherein the vector is a plasmid.
Claims 1-5, 8, 11-12, 14-17 & 20-23 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for - A recombinant Aspergillus niger, comprising an exogenous nucleic acid molecule encoding aspartate 1-decarboxylase (PAND), an exogenous nucleic acid molecule encoding β-alanine-pyruvate aminotransferase (BAPAT), and an exogenous nucleic acid molecule encoding 3- hydroxypropionate dehydrogenase (HPDH), wherein: i) the PAND comprises at least 95% sequence identity to SEQ ID NO: 1; ii) the BAPAT comprises at least 95% sequence identity to SEQ ID NO: 2; and iii) the HPDH comprises at least 95% sequence identity to SEQ ID NO: 3; wherein the exogenous nucleic acid molecules encoding PAND, BAPAT, and HPDH are encoded by a nucleic acid molecule comprising at least 95% sequence identity to SEQ ID NO: 4 and/or SEQ ID NO: 142, or a nucleic acid molecule comprising or consisting of SEQ ID NO: 4 and/or SEQ ID NO: 142 & methods thereof, does not reasonably provide enablement for a recombinant Aspergillus niger, comprising an exogenous nucleic acid molecule encoding aspartate 1-decarboxylase (PAND), an exogenous nucleic acid molecule encoding β-alanine-pyruvate aminotransferase (BAPAT), and an exogenous nucleic acid molecule encoding 3- hydroxypropionate dehydrogenase (HPDH) & methods thereof, all being from any source and with no defined structure/sequence.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
According to MPEP 2164.01(a), factors considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
MPEP§ 2164.04 states that while the analysis and conclusion of a lack of enablement are based on the factors discussed in MPEP § 2164.01(a) and the evidence as a whole, it is not necessary to discuss each factor in the written enablement rejection. The language should focus on those factors, reasons, and evidence that lead the examiner to conclude that the specification fails to teach how to make and use the claimed invention without undue experimentation, or that the scope of any enablement provided to one skilled in the art is not commensurate with the scope of protection sought by the claims. Accordingly, the factors most relevant to the instant rejection are addressed in detail below.
The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of exogenous nucleic acid molecule encoding aspartate 1-decarboxylase (PAND), an exogenous nucleic acid molecule encoding β-alanine-pyruvate aminotransferase (BAPAT), and an exogenous nucleic acid molecule encoding 3-hydroxypropionate dehydrogenase (HPDH), used in the making of recombinant Aspergillus niger broadly encompassed by the claims. Since the amino acid sequence of a protein determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence, if any, are tolerant of modification and which are conserved (i.e. expectedly intolerant to modification), and detailed knowledge of the ways in which the proteins' structure relates to its function.
However, in this case the disclosure is limited to the nucleotide sequence of SEQ ID NO: 4/142 and encoded amino acid sequences of SEQ ID NOs: 1-3.
While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple modifications, as encompassed by the instant claims, and the positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass A. niger recombinantly produced to include aspartate 1-decarboxylase (PAND), β-alanine-pyruvate aminotransferase (BAPAT), and 3-hydroxypropionate dehydrogenase (HPDH) from any source with the limited guidance provided.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including A. niger recombinantly produced to include aspartate 1-decarboxylase (PAND), β-alanine-pyruvate aminotransferase (BAPAT), and 3-hydroxypropionate dehydrogenase (HPDH) and the encoding DNA from any source. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of the numerous DNA encoding aspartate 1-decarboxylase (PAND), β-alanine-pyruvate aminotransferase (BAPAT), and 3-hydroxypropionate dehydrogenase (HPDH) having the desired biological characteristics or methods thereof is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
8. 35 U.S.C. § 112, first paragraph (Written Description)
Claims 1-5, 8, 11-12, 14-17 & 20-23 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention is broadly directed to A recombinant Aspergillus niger, comprising an exogenous nucleic acid molecule encoding aspartate 1-decarboxylase (PAND), an exogenous nucleic acid molecule encoding β-alanine-pyruvate aminotransferase (BAPAT), and an exogenous nucleic acid molecule encoding 3- hydroxypropionate dehydrogenase (HPDH) or methods thereof.
The claims are described by functional limitations only (see above - claims in paragraph 7) and are devoid of a reference structure for the claimed amino acid or nucleic acid. The claimed invention encompasses a genus of amino acids/nucleic acids not adequately described.
The instant specification describes “A recombinant Aspergillus niger, comprising an exogenous nucleic acid molecule encoding aspartate 1-decarboxylase (PAND), an exogenous nucleic acid molecule encoding β-alanine-pyruvate aminotransferase (BAPAT), and an exogenous nucleic acid molecule encoding 3- hydroxypropionate dehydrogenase (HPDH), wherein: i) the PAND comprises at least 95% sequence identity to SEQ ID NO: 1; ii) the BAPAT comprises at least 95% sequence identity to SEQ ID NO: 2; and iii) the HPDH comprises at least 95% sequence identity to SEQ ID NO: 3; wherein the exogenous nucleic acid molecules encoding PAND, BAPAT, and HPDH are encoded by a nucleic acid molecule comprising at least 95% sequence identity to SEQ ID NO: 4 and/or SEQ ID NO: 142, or a nucleic acid molecule comprising or consisting of SEQ ID NO: 4 and/or SEQ ID NO: 142 & methods thereof”.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
"To fulfill the written description requirement, a patent specification must describe aninvention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what isclaimed."). Thus, an applicant complies with the written description requirement "bydescribing the invention, with all its claimed limitations, not that which makes it obvious,"and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966."Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents" of the University of California v. Eli Lilly & Co. the court stated:
"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., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is "not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence." MPEP § 2163. The MPEP does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the 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. While all of the factors have been considered, a sufficient amount for a prima facie case is discussed below.
Further, to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include: a) the scope of the invention; b) actual reduction to practice; c) disclosure of drawings or structural chemical formulas; d) relevant identifying characteristics including complete structure, partial structure, physical and/or chemical properties, and structure/function correlation; e) method of making the claimed compounds; f) level of skill and knowledge in the art; and g) predictability in the art.
Moreover, Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir.1991), states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed" (See page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed" (See Vas-Cath at page 1116). The skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993).
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
9. 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, 8 & 12 is/are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by US 10947548 B2.
US 10947548 B2 teaches methods of making 3-hydroxypropionic acid (3-HP using the disclosed Aspergillus ΔcadA strains that also expresses panD, BAPAT, and HPDH (which can be exogenous). For example, such a method can include culturing an isolated ΔcadA Aspergillus that also expresses panD, BAPAT, and HPDH under conditions that permit the fungus to make 3-HP, thereby producing 3-HP. Such panD, BAPAT, and HPDH nucleic acid molecules can be part of a vector. In addition, expression of the panD, BAPAT, and HPDH can be driven by one or more promoters. See paragraph 7 & 11 of the Summary section. Figures 2-6 shows the expression of panD, BAPAT, and HPDH in Aspergillus ΔcadA strains and is compared with wild-type. Expression of one or more genes in hetereologous hosts, including E. coli, A. niger, and S. cerevisiae, can result in the production of itaconic acid in non-itaconic acid host microorganisms ( See Paragraph 3). The reference anticipates the claims.
10. Claims 6-7 & 9-10 are objected to and depend on rejected base claim(s) but will be allowable if written in independent form including all the limitations of the base claim(s).
11. Claims 1-5, 8, 11-12, 14-17 & 20-23 are rejected. Claim 13 is withdrawn.
12. 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