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 .
Support for the amendments and new claims is within the instant application specification.
Applicants’ amendment to the claims filed on 6/30/2023 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
New claims 36-44 are added.
Claims 1-22, 34-35 are cancelled.
Claims 23-33, 36-44 are pending and examined on the merits.
Priority
Acknowledgement is made of this national stage entry of PCT/US2022/012644 of Non-provisional Application No. 18/260,225, filed on 1/15/2022 which claims domestic priority to U.S. provisional application 63/138,495, filed on 1/17/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 2/21/2025, 6/30/2023 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The Drawings filed on 6/30/2023 are acknowledged and accepted by the Examiner.
Claim Rejections - 35 USC § 112
The 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.
Scope of Enablement
Claims 23-33, 36-44 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for cells in which 6ACA importer gene is not disabled, it does not provide enablement for cells where the importer of 6ACA is disabled. It is the Examiner’s position that it would be counter-productive to use a cell in which the gene for importing 6ACA into the cells is not disabled because although the cell in claim 26 (claim 27 dependent thereof), has an exogenous exporter to export 6ACA to the outside of the cell, the same cell having the 6ACA import gene would bring it back in to the cell thereby not enabling the method of the instant application. It is recommended that Applicant amend the claim to add the limitation of claim 26 in to independent claim 23, that said cell is negative for the 6ACA importer gene. As such, 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 and/or use the invention commensurate in scope with these claims.
The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (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. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
(A)The breadth of the claims:
Claims 23-33, 36-44 are drawn to a method for making a 6-aminocaproic acid, comprising the steps of: providing a non-naturally occurring microbial organism comprising a pathway for making a 6-aminocaproic acid and an exogenous nucleic acid encoding a transporter for the 6- aminocaproic acid, wherein the exogenous transporter exports the 6-aminocaproic acid from the cell; and culturing the non-naturally occurring microbial organism in a medium under conditions where the 6-aminocaproic acid is produced. The structure of a cells that both imports and exports 6-aminocaproic acid is counterproductive, thereby is not enabled by the methods of the instant application.
B) The nature of the invention; C)The state of the prior art; (D) The level of one of ordinary skill; and (E) The level of predictability in the art: As noted above, the scope of the claimed cell that both import and exports 6-aminocaproic acid is counterproductive to the method of the invention.
In this regard, it is noted that the reference of Cleves (1997, Dispatch, Examiner cited) discloses Several proteins that lack a classical secretory signal sequence are transported out of mammalian cells (column 1, para 1). This atypical secretion, termed ‘nonclassical export’, occurs by poorly understood mechanisms that are independent of the classic vesicular secretory pathway. Interestingly, many of the same proteins that are exported by nonclassical mechanisms can also be imported into cells by unconventional means (column 1, para 1). As such, said process would not result in the accumulation of protein in culture medium.
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The specification discloses the following working example of a cell wherein an importer of 6-ACA is not disabled while an exporter of 6-ACA is enabled (i.e. SEQ ID NO: 1. 3. 17. 19, 21, 23, 25, 27, 29, 31, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, and/or 93). Other than the above disclosed species, there is no prior-art or disclosed teaching as to the number of cells wherein an importer of 6-ACA is not disabled while an exporter of 6-ACA is enabled.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, the state of the prior art, and counterproductivity, undue experimentation, would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. 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. 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 having the desired biological characteristics 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).
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 24,-27, 29-33, 37, 39-44 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 24 (claims 26, 27, 37, 39, 40, 41, 42, 43, 44 dependent thereof) are rejected as it recites the same limitations of claim 23, which is “wherein the exogenous transporter exports…from the cell.” Therefore the limitation of claim 24 which recites, ‘further comprising the step of transporting the 6-aminocaproic acid from the microbial organism into the medium’ is not further limiting. Examiner is unable to distinguish any differences between the terms “exports” and “transports.” Appropriate correction is suggested.
Claim 41 (claims 42-44 dependent thereof) are rejected as it recites the same limitations of claim 39, which is “wherein the non-naturally occurring microbial organism further comprising an exogenous nucleic acid encoding a glutamate dehydrogenase.” Therefore the limitation of claim 41 which recites, ‘wherein the non-naturally occurring microbial organism further comprising an exogenous nucleic acid encoding a glutamate dehydrogenase’ is not further limiting. Appropriate correction is suggested.
Claims 25, 37 attempts to incorporate by reference the transporters recited in Table 16 of the specification. However, as clearly noted in M.P.E.P. 2173.05(s), this kind of reference to table or figures is only permitted when there is no way to clearly describe the content of the table or figure in words within the claim. It is not, however, permitted merely for Applicant’s convenience.
It is noted that the different transporters of Table 16 and their UniprotKB Accession numbers can be listed in the claim in order to overcome the instant rejection.
The phrase “at least some” in claim 30 is a relative term which renders the claim indefinite. The term “at least some” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear the limitation of the phrase “at least some” recited in claim 30. It is unclear the amount of glutamate made by the glutamate dehydrogenase is used by a transaminase that produces the 6-aminocaproic acid. Appropriate correction is suggested.
Claims 31, 32, 33, 42, 43 attempts to incorporate by reference the glutamate dehydrogenases recited in Table 17 of the specification. However, as clearly noted in M.P.E.P. 2173.05(s), this kind of reference to table or figures is only permitted when there is no way to clearly describe the content of the table or figure in words within the claim. It is not, however, permitted merely for Applicant’s convenience.
The different transporters of Tables 16-17 and their UniprotKB Accession numbers can be listed in the claim in order to overcome the instant rejection.
It is noted that the 6ACA transporters listed in table 16 do not all encompass the claimed limitation of having a relative 6ACA export activity of ‘greater than 1.10’ (claim 25), ‘a relative 6ACA export activity of greater than 0.80’ (claim 37), based on Applicant’s own disclosure in table 16 of the instant application specification. It is suggested that Applicant amend the claims to recite the 6ACA transporters that exhibits the limitations of claims 25, 37.
It is noted that the GDH (glutamate dehydrogenase) listed in table 17 do not all encompass the limitation of ‘an in vitro activity with NADH or NADPH of greater than 100 AF/min’ (claims 31, 42), ‘an in vitro activity with NADH or NADPH of 100-500 AF/min’ (claims 32, 43), ‘an in vitro activity with NADH or NADPH of greater than 500 AF/min’ (claim 33) based on Applicant’s own disclosure in table 17 of the instant application specification. It is suggested that Applicant amend the claim to recite the glutamate dehydrogenase that exhibits the limitations of claims 31, 32, 33, 42, 43.
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.
Claims 23-24, 26, 28, 30, 36, 39, 41 are rejected under 35 U.S.C. 103 as being unpatentable over Burgard et al (US 2009/0305364 A1, Date Published: Dec. 10, 2009, Examiner cited) {herein Burgard} as evidenced by Plaitakis et al (2017, biology review, Examiner cited).
Claims 23-24, 26, 28, 30, 36, 39, 41 are drawn to a method for making a 6-aminocaproic acid, comprising the steps of: providing a non-naturally occurring microbial organism comprising a pathway for making a 6-aminocaproic acid and an exogenous nucleic acid encoding a transporter for the 6- aminocaproic acid, wherein the exogenous transporter exports the 6-aminocaproic acid from the cell; and culturing the non-naturally occurring microbial organism in a medium under conditions where the 6-aminocaproic acid is produced.
With respect to claims 23-24, 26, 36 Burgard teaches a method wherein a non-naturally occurring organism comprises a pathway for making 6-aminocaproic acid (abstract). The non-naturally occurring microbial organisms comprises at least one exogenous nucleic acid encoding a transaminase enzyme that reacts with adipate semialdehyde to form 6-aminocaproic acid (6ACA) (para 0041). Said exogenous nucleic acid is transformed into host cell MG1655 E. coli (para 0032, 0187). The methods include culturing the non-naturally occurring microbial organisms in medium under conditions and for a sufficient period of time to produce 6-aminocaproic acid (Burgard: claim 49).
With respect to claim 36, Burgard teaches a method wherein the production of 6-aminocaproic
acid is increased through exogenous expression of the endogenous gene or genes, or through exogenous expression of the heterologous gene or genes (para 0056).
With respect to claims 28, 30, 39, 41, Burgard teaches a method wherein a transaminase transfers an amino acid from glutamate to the terminal aldehyde of succinyl semialdehyde for the synthesis of 6-aminocaproic acid (para 0179). As such, it is the Examiner’s opinion, that is would be obvious to one of ordinary skill in the art to add an exogenous nucleic acid encoding a glutamate dehydrogenase as said construct would result in an ample supply of glutamate for the synthesis of 6-aminocaproic acid.
However, Burgard does not teach the method of claim 1 of an exogenous nucleic acid encoding a transporter for the 6- aminocaproic acid (claim 23). The method of claim 24, further comprising the step of transporting the 6-aminocaproic acid from the microbial organism into the medium (claim 24). The method of claim 26, wherein the non-naturally occurring microbial organism further comprising a disruption of a gene encoding a transporter that imports 6-aminocaproic acid into the microbial organism (claim 26). T
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to modify the method for the making a 6-aminocaproic acid, taught by Burgards, by including an exogenous nucleic acid encoding a transporter for the 6- aminocaproic acid (instant application claim 23) because it would allow for better control of the export of 6-aminocaproic acid out of the cell thereby making purification of the molecule easier and subsequently reducing the costs associated with manufacturing high volumes of said molecule. Absent evidence otherwise, it is the Examiner’s opinion that the step of ‘transporting the 6-aminocaproic acid from the microbial organism into the medium’ (claim 24) would be inherent in the presence of an exporter for 6-aminocaproic acid. Furthermore, it would be obvious to one of ordinary skill in the art to modify the method of making 6-aminocaproic acid, taught by Burgard, by disrupting an importer of 6-aminocaproic acid (claim 26) and if said genes remained active, it would likely reduce the yield of 6-aminocaproic acid in medium, thereby requiring a step of lysing the host cells in order to purify 6-aminocaproic acid from cells. Said lysing could result in the accumulation of cellular artifacts in the resulting yield of 6-aminocaproic acid in medium resulting in the need for further purification. One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability, and would be motivated to add an exogenous nucleic acid encoding a transporter to a non-naturally occurring microorganism comprising a pathway for making 6-aminocaproic acid because doing so would increase the extracellular yield of 6-aminocaproic acid and would allow for its ease in purification for the production of pharmaceuticals to treat cancers. Furthermore, one of ordinary skill in the art would be motivated to disrupt a gene encoding a transporter that imports 6-aminocaproic acid into the microbial organism as doing so would increase the extracellular yield of 6-aminocaproic acid by inhibiting or limiting its importation from medium into the cell. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
Status of the claims
Claims 23-33, 36-44 are pending.
Claims 1-22, 34-35 are cancelled.
Claims 23-33, 36-44 are rejected
No claims are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERICA NICOLE JONES-FOSTER whose telephone number is (571)270-0360. The examiner can normally be reached mf 7:30a - 4:30p.
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, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERICA NICOLE JONES-FOSTER/Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656