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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/29/2025 has been entered.
Claim Status
The amendment of 12/29/2025 has been entered. Claims 7 and 9-26 are pending (claim set as filed on 12/29/2025). Claims 9-20 and 23-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election of invention Group I, drawn to a modified phenylalanine dehydrogenase and of the mutation species N290D was made without traverse in the reply filed on 11/20/2024.
Claims 7 and 21-22 are currently under examination and were examined on their merits.
Withdrawn Objections/Rejections
The rejection of claims 7 and 21-22 under 35 U.S.C. 103 set forth in the previous Office action has been withdrawn in light of Applicant’s Declaration under 37 CFR 1.132 filed on 11/07/2025. The results presented in the declaration provide evidence that a modified phenylalanine dehydrogenase comprising a mutation of N290D has an improved substrate specificity to phenylalanine relative to a wild-type. However, it is suggested that applicant files an IDS that lists the recited NPL reference ‘Sensors and Materials, Vol. 36, No. 8 (2024) 3201-3210’ for full consideration of said reference and Declaration.
Claim Rejections - 35 USC § 112(a)
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.
Claims 7 and 21-22 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.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. Claims 7 and 21-22 are directed in part to a genus of phenylalanine dehydrogenase variants that have an amino acid sequence comprising deletion or insertion of one to thirty-five amino acid residues in the amino acid sequence of SEQ ID NO: 1.
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.
There is either (a) no structural limitation, or (b) a significant amount of structural variability with respect to the members of the genus of phenylalanine dehydrogenase variants that have an amino acid sequence comprising deletion or insertion of one to thirty-five amino acid residues in the amino acid sequence of SEQ ID NO: 1 required by the claims. While the specification in the instant application discloses the structure of SEQ ID NO: 1, and specific substitutions and N-terminal additions (His-tag), it provides no clue as to the structural elements required in any phenylalanine dehydrogenase protein, nor does it teach which structural elements within SEQ ID NO: 1 are required in any protein. Moreover, while the claims require modified phenylalanine dehydrogenase variants comprising a mutation of N290D relative to a wild-type phenylalanine dehydrogenase comprising a deletion or insertion of 1-35 amino acid residues in the amino acid sequence of SEQ ID NO: 1 having enhanced functional properties, the specification and the prior art are silent to deletions and insertions in any phenylalanine dehydrogenase protein that are associated with phenylalanine dehydrogenase functional properties. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which variants of the polypeptide of SEQ ID NO: 1 carrying deletions or insertions have phenylalanine dehydrogenase activity and functional properties.
It is noted that due to the unspecified deletions or insertions in the amino acid sequence of SEQ ID NO: 1, the claims encompass a large genus of proteins which are structurally unrelated or substantially unrelated in structure. A sufficient written description of a genus of polypeptides may be achieved by a recitation of a representative number of polypeptides defined by their amino acid sequence or a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. However, in the instant case, there is either no recited structural feature which is representative of all the members of the genus of proteins recited, or the recited structural feature, i.e., amino acid sequence comprising deletion or insertion of one to thirty-five amino acid residues in the amino acid sequence of SEQ ID NO: 1, is not representative of all the members of the genus of phenylalanine dehydrogenases recited since there is no information as to which are the structural elements within the polypeptide of SEQ ID NO: 1 that are essential for the recited activity, which are the remaining structural elements required in the recited polypeptides in addition to those recited in the claims such that the desired phenylalanine dehydrogenase activity is displayed, or a correlation between structure and function which would provide those unknown structural features.
Due to the fact that the specification does not disclose any sequences of the genus of phenylalanine dehydrogenase proteins having an amino acid sequence comprising deletion or insertion of one to thirty-five amino acid residues in the amino acid sequence of SEQ ID NO: 1 required by the claims, and the lack of description of any additional species by any relevant, identifying characteristics or properties, one of skill in the art would not recognize from the disclosure that applicant was in possession of the claimed invention.
Claim 22 is 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 improved phenylalanine dehydrogenase activity of modified phenylalanine dehydrogenases according to embodiment (ii) of base claim 7, does not reasonably provide enablement for a modified phenylalanine dehydrogenase comprising a mutation of N290D according to embodiment (i) of base claim 7, having improved phenylalanine dehydrogenase activity relative to a phenylalanine dehydrogenase consisting of the amino acid sequence of SEQ ID NO: 1. 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.
In evaluating the enablement question, several factors are to be considered. Note In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1998).
The factors include MPEP (2164.01):
(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.
The determination that ‘undue experimentation’ would have been needed to use the claimed invention is not a single simple factual determination. Rather, it is a conclusion weighing all the above noted factual considerations (see MPEP2164.01).
Regarding the breadth of the claim and the nature of the invention, the instant claim is drawn to a modified phenylalanine dehydrogenase relative to a wild-type phenylalanine dehydrogenase, comprising a mutation of N290D according to the embodiment (i) of base claim 7, said modified phenylalanine dehydrogenase having an improved characteristic relative to a phenylalanine dehydrogenase consisting of the amino acid sequence of SEQ ID NO: 1, wherein said characteristic is selected from the group consisting of: i) solubility, ii) phenylalanine dehydrogenase activity, and iii) combinations thereof.
Regarding the state of the prior art of a modified phenylalanine dehydrogenase comprising a mutation of N290D, Tatsumi et al. (“Improved Substrate Specificity of Phenylalanine Dehydrogenase for L-Phenylalanine Sensor”, published in 2024, Sensors and Materials, Vol. 36, No. 8, pages 3201-3210), hereinafter ‘Tatsumi’, teaches wherein “the activity of the PheDH N290D mutant toward L-Phe was reduced to 53.8% of that of the wild-type PheDH” (page 3206, lines 20-22).
Regarding the skill level of one of ordinary skill in the art, the skill level of one of ordinary skill in the art of modifying enzymes by amino acid substitution is considered high.
Regarding the predictability of the art of amino acid substitutions to increase activity in phenylalanine dehydrogenase, the above listed modified phenylalanine dehydrogenase is complex, and the effects of amino acid substitutions on enzyme activity are considered unpredictable.
Regarding direction provided by the applicant, the applicant discloses how to introduce mutations to a phenylalanine dehydrogenase (paragraph [000324]), but does not disclose additional features required to obtain a modified phenylalanine dehydrogenase comprising a mutation of N290D according to embodiment (i) of base claim 7 having improved phenylalanine dehydrogenase activity relative to a phenylalanine dehydrogenase consisting of the amino acid sequence of SEQ ID NO: 1.
Regarding working examples, Applicant provides working examples showing modified phenylalanine dehydrogenases comprising a mutation of N290D according to embodiment (ii) of base claim 7 having improved phenylalanine dehydrogenase activity relative to a wild-type phenylalanine dehydrogenase, but no working examples of phenylalanine dehydrogenase comprising a mutation of N290D according to embodiment (i) of base claim 7 are provided that demonstrate improved phenylalanine dehydrogenase activity (see Tables 12 and 13) .
From the experiments and data presented in the instant case, it is not possible to know how to further modify the phenylalanine dehydrogenase comprising a mutation of N290D according to embodiment (i) of base claim 7 in order to obtain improved phenylalanine dehydrogenase activity.
In face of the challenging and unpredictable nature of amino acid substitutions to increase phenylalanine dehydrogenase activity, the lack of specific guidance on additional modifications of the phenylalanine dehydrogenase comprising a mutation of N290D according to embodiment (i) of base claim 7, and the lack of appropriate working examples that describe a modified phenylalanine dehydrogenase according to embodiment (i) of base claim 7, undue experimentation would be required from one of ordinary skill in the art to develop a phenylalanine dehydrogenase comprising a mutation of N290D according to embodiment (i) of base claim 7 that has improved phenylalanine dehydrogenase activity relative to a phenylalanine dehydrogenase consisting of the amino acid sequence of SEQ ID NO: 1, as claimed by applicant, since the prior art teaches wherein the activity of a phenylalanine dehydrogenase comprising a N290D mutation has reduced activity compared to the wild-type.
Closest prior art
Regarding claims 7 and 21-22, the closest prior art to the claimed invention is provided
by the teachings of Ayyub et al. (US 2016/0168613 A1, published on 06/16/2016).
Ayyub teaches a modified phenylalanine dehydrogenase relative to a wild-type phenylalanine dehydrogenase, comprising a mutation (paragraphs [0019], [0123], [0171]);
wherein the wild-type phenylalanine dehydrogenase comprises
(A) the amino acid sequence of instant SEQ ID NO: 1 (paragraph [0018]; see Table on page 15 and SEQ ID NO: 2 on pages 15 and 29; note, Ayyub’s SEQ ID NO:2 is identical with instant SEQ ID NO: 1),
wherein said modified phenylalanine dehydrogenase has a phenylalanine dehydrogenase activity (paragraph [0018]). Ayyub further teaches wherein the substrate of a phenylalanine dehydrogenase is phenylalanine (see Fig. 13), and that “[e]nzyme activity will be improved, if necessary, by site directed mutagenesis to increase the affinity for the substrates or the stability”; paragraph [0171]), thereby indicating that a modified phenylalanine dehydrogenase has phenylalanine dehydrogenase activity, which is improved relative to the wild-type phenylalanine dehydrogenase.
Ayubb does not teach wherein the modified phenylalanine dehydrogenase comprises a mutation of N290D, and wherein the modified phenylalanine dehydrogenase has an improved substrate specificity to phenylalanine relative to the wild-type phenylalanine dehydrogenase.
Conclusion
No claims are allowed.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA ZINGARELLI whose telephone number is (703)756-1799. The examiner can normally be reached M-F 9-5.
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/SANDRA ZINGARELLI/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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